Protecting oral overdose with abuse deterrent immediate release formulations

ABSTRACT

The invention relates to a pharmaceutical dosage form which is particularly useful for the prevention of an overdose of the pharmacologically active ingredient contained therein after accidental or intentional simultaneous administration of a plurality of the dosage forms containing an overall supratherapeutic dose of the pharmacologically active ingredient.

This application is a continuation of U.S. Ser. No. 15/260,643, filedSep. 9, 2016, now allowed, which claims priority of European patentapplication no. 15 184 634.2 that was filed on Sep. 10, 2015.

The invention relates to a pharmaceutical dosage form which isparticularly useful for the prevention of an overdose of thepharmacologically active ingredient contained therein after accidentalor intentional simultaneous administration of a plurality of the dosageforms containing an overall supratherapeutic dose of thepharmacologically active ingredient.

A large number of drugs have a potential for being abused or misused,i.e. they can be used to produce effects which are not consistent withtheir intended use. Examples of commonly abused drugs includepsychoactive drugs, anxiolytics, sedative hypnotics, stimulants,depressants, and analgesics such as narcotic analgesics, among others.In particular, drugs which have a psychotropic effect, e.g. opioids,morphine derivatives, barbiturates, amphetamines, ketamine, and otherdrugs, are abused to induce euphoric states similar to beingintoxicated, and can cause psychological or physical dependence.

Some common techniques for intentionally abusing a drug begin with anabuser obtaining a solid dosage form such as an orally administeredtablet or capsule, and crushing the solid dosage form into a powder. Thepowder may be administered by an abuser by nasal insufflation (i.e.,“snorting”) to introduce the drug to the abuser's bloodstreamintranasally. Alternately, the crushed dosage form may be combined witha solvent that is capable of dissolving the drug, and the solvent withthe dissolved drug may be injected directly into an abuser'sbloodstream. This type of administration results in an even fasterdiffusion of the drug compared to the oral abuse, with the resultdesired by the abuser, namely the kick.

Various concepts for the avoidance of drug abuse have been developed. Ithas been proposed to incorporate in dosage forms aversive agents and/orantagonists in a manner so that they only produce their aversive and/orantagonizing effects when the dosage forms are tampered with. However,the presence of such aversive agents, e.g. bitter substances, irritants,colorants, emetics, and the like is principally not desirable and thereis a need to provide sufficient tamper-resistance without relying onaversive agents and/or antagonists.

Another concept to prevent abuse relies on the mechanical properties ofthe pharmaceutical dosage forms, particularly an increased breakingstrength (resistance to crushing). The mechanical properties,particularly the high breaking strength of these pharmaceutical dosageforms renders them tamper-resistant. The major advantage of suchpharmaceutical dosage forms is that comminuting, particularlypulverization, by conventional means, such as grinding in a mortar orfracturing by means of a hammer, is impossible or at least substantiallyimpeded. Thus, the pulverization, necessary for abuse of the dosageforms, by the means that are usually available to a potential abuser isprevented or at least complicated. Such pharmaceutical dosage forms areuseful for avoiding drug abuse of the drug contained therein, as theymay not be powdered by conventional means and thus, cannot beadministered in powdered form, e.g. nasally. In the context of suchbreak resistant pharmaceutical dosage forms it can be referred to, e.g.,WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO2006/002883, WO 2006/002884, WO 2006/002886, WO 2006/082097, WO2006/082099, WO 2008/107149, WO 2009/092601, WO 2011/009603, WO2011/009602, WO 2009/135680, WO 2011/095314, WO 2012/028317, WO2012/028318, WO 2012/028319, WO 2011/009604, WO 2013/017242, WO2013/017234, WO 2013/050539, WO 2013/127830, WO 2013/072395, WO2013/127831, WO 2013/156453, WO 2013/167735, WO 2015/004245, WO2014/191396, and WO 2014/191397.

Still another concept to prevent abuse relies on the presence ofauxiliary substances that increase the viscosity of the resultantcomposition when the dosage forms are tampered with, e.g. when they aresubjected to liquids in order to prepare formulations for parenteraladministration, e.g. intravenous injection. Said auxiliary substancesincrease the viscosity of the resultant compositions to such an extentthat the liquids cannot be drawn-up in syringes. While it may bepossible to extract the drug from the dosage form at least to a certainextent, the extract is not useful for subsequent abuse.

WO 2015/103379 A1 discloses abuse-resistant, immediate-release liquidpharmaceutical compositions comprising a mixture of an effective amountat least one pharmaceutically active agent susceptible to abuse, anorganic vehicle, a surfactant, a co-solvent, and optionally aviscosity-building polymer; wherein said organic vehicle, surfactant,and co-solvent co-elute with the pharmaceutically active agent whenexposed to a solvent, and wherein the viscosity-building polymer ispresent in an amount that slows the release of the pharmaceuticallyactive agent if multiple unit doses of the composition are administered.The compositions shall reduce the likelihood of improper administrationof drugs that are susceptible to abuse. The compositions contain abusedeterrent agents that cause discomfort to the user when administered inan improper manner and make the extraction of an active ingredient moredifficult.

Alternatively, with immediate release oral dosage forms, an abuser mightsimply ingest multiple units (e.g., tablets) of the dosage formtogether, e.g., simultaneously. Each one of the multiple dosage formunits—immediately releases an amount of drug to produce a short-termconcentration spike of the drug in the user's bloodstream and a desired“high” in the user.

WO 2008/107149 discloses a multiparticulate pharmaceutical form withimpeded abuse including at least one active ingredient with thepotential for abuse (A), at least one synthetic or natural polymer (C),optionally at least one natural, semi-synthetic, or synthetic wax (D),at least one disintegrant (E), and optionally one or more additionalphysiologically tolerable excipients (B), wherein the individualparticles of the pharmaceutical form have a breaking strength of atleast 500 N and an active ingredient release of at least 75% after 45minutes, measured according to Pharm. Eur. in the paddle mixer with asinker in a 600 ml aqueous buffer solution with a pH value of 1.2 at 37°C. and 75 revolutions per minute.

WO 2013/017242 and WO 2013/017234 relate to a tamper-resistant tabletcomprising a matrix material in an amount of more than one third of thetotal weight of the tablet; and a plurality of particulates in an amountof less than two thirds of the total weight of the tablet; wherein saidparticulates comprise a pharmacologically active compound and apolyalkylene oxide; and form a discontinuous phase within the matrixmaterial.

US 2015 0118300 A1 discloses oral dosage forms that containabuse-deterrent features and that contain core-shell polymers thatinclude an active pharmaceutical ingredient, with particular examplesincluding immediate release dosage forms that contain a drug that iscommonly susceptible to abuse.

US 2015 0118302 A1 and US 2015 0118303 A1 disclose immediate releaseoral dosage forms that contain abuse-deterrent features. In particular,the disclosed dosage forms provide deterrence of abuse by ingestion ofmultiple individual doses. In addition, the disclosed dosage formsprovide protection from overdose in the event of accidental orintentional ingestion of multiple individual doses. The dosage formshave a relatively complex construction of a) core-shell particlescomprising: a core; an active pharmaceutical layer surrounding the core;at least one layer surrounding the active pharmaceutical layer, the atleast one layer comprising a pH-sensitive film comprising pH-sensitivepolymer that is insoluble in water at a pH greater than 5 and is solublein water at a pH below 5; and b) a matrix comprising a disintegrant anda gelling polymer.

The properties of conventional tamper-resistant dosage forms are notsatisfactory in every respect. The requirements for tamper-resistantdosage forms that nowadays need to be satisfied are complex andsometimes are difficult to be combined and arranged with one another.While a certain measure may improve tamper-resistance in a certainaspect, the same measure may deteriorate tamper-resistance in anotheraspect or otherwise may have a detrimental effect on the properties ofthe dosage forms.

Although the pharmaceutical industry has identified a variety of abusedeterrent features useful with oral dosage forms, there is continuingneed to improve and identify new abuse deterrent features to inhibit orprevent abuse or overdosing of active pharmaceutical ingredients.

It is an object of the invention to provide pharmaceutical dosage formshaving advantages compared to the pharmaceutical dosage forms of theprior art. The pharmaceutical dosage forms should be particularly usefulfor avoiding or preventing of an overdose of the pharmacologicallyactive ingredient contained therein after accidental or intentionalsimultaneous administration of a plurality of the dosage formscontaining an overall supratherapeutic dose of the pharmacologicallyactive ingredient.

This object has been achieved by the subject-matter of the patentclaims.

A first aspect of the invention relates to a pharmaceutical dosage formcomprising a pharmacologically active ingredient a and a polymer matrixwhich comprises a polyalkylene oxide having an average molecular weightof at least 200,000 g/mol; preferably of at least 500,000 g/mol;

wherein preferably a single dosage form provides under physiologicalconditions fast release, more preferably immediate release of thepharmacologically active ingredient a; andwherein at least a portion of the pharmacologically active ingredient ais contained in one or more particles A which comprise the polymermatrix in which the pharmacologically active ingredient a is embedded;for use in the prevention of an overdose of the pharmacologically activeingredient a after accidental or intentional simultaneous administrationof a plurality of the dosage forms containing an overallsupratherapeutic dose of the pharmacologically active ingredient a.

Preferably, the overdose that is to be prevented is the result of anaccidental or intentional simultaneous oral administration of aplurality of not-manipulated dosage forms, i.e. the plurality of dosageforms is preferably intact and with respect to an individual dosage formpresent in prescribed form. Preferably, the only deviation from theprescribed mode of administration and prescribed route of administrationis the number of the administered dosage forms, namely a plurality ofthe dosage forms containing an overall supratherapeutic dose of thepharmacologically active ingredient a.

It has been surprisingly found that the dosage forms according to theinvention provide deterrence against abuse by multi-tablet dosing(multi-dosage-form-dosing). More specifically, in vitro testing ofdosage forms was performed by conducting dissolution testing of one ormore dosage forms (tablets) in various volumes of 0.1N HCL maintained at37° C. using a 25 rpm and 50 rpm paddle speed. At 25 rpm the amount(percentage per tablet) of pharmaceologically active ingredient a(opioid) and pharmacologically active ingredient b (acetaminophen)released in the media is reduced with an increase in the number oftablets, whereas at 50 rpm this effect was less pronounced or could notbe observed. The mixing conditions at 25 rpm are still not comparablewith the conditions in the gastrointestinal tract under in vivoconditions (J. L. Baxter et al., Int J Pharm 292 (2005) 17-28; M.Koziolek et al., Eur J Pharm Sci 57 (2014) 250-256). Under in vivoconditions in the stomach pharmaceutical dosage forms are not subject torotational movement but to compression forces. The data suggest that thedosage forms according to the invention are effective to preventincreased levels of drug uptake in an individual who would accidentallyor intentionally ingest multiple tablets, preventing or reducing therisk of an intentional or unintentional overdose of the drug.

Accordingly, the dosage forms according to the invention provide amethod of preventing a short-term concentration spike of the drug in thebloodstream of a patient who is prescribed the drug, or in thebloodstream of an abuser who consumes the drug for recreationalpurposes, in the event that a patient or the abuser intentionally orunintentionally consumes a supratherapeutic dose of the drug. Inaddition, dosage forms as described herein provide a method whereby adrug overdose may be prevented in the event that a patient intentionallyor unintentionally consumes a supratherapeutic dose of the drug. By“supratherapeutic” is meant a dose that exceeds what would normally beprescribed for therapy, for example a dose in excess of four, five, six,seven, eight, nine, ten, eleven or twelve individual dose units (e.g.,tablets, capsules, etc.).

Thus, the dosage form as according to the invention are useful for theprevention of an overdose of the pharmacologically active ingredient aafter accidental or intentional simultaneous preferably oraladministration of a plurality of the dosage forms containing an overallsupratherapeutic dose of the pharmacologically active ingredient a.

Unexpectedly, the advantages of the dosage form according to theinvention do not only affect the pharmacologically active ingredient athat is embedded in the polyalkylene oxide in particle(s) A, but alsothe optionally present pharmacologically active ingredient b that may bepresent elsewhere in the dosage form.

It has been surprisingly found that these advantages can be achieved bydosage forms that additionally are crush resistant, i.e. have anincreased breaking strength, at least with respect to particle(s) Acomprising the pharmacologically active ingredient a.

Some tamper-resistant dosage forms of the prior art have also been usedto avoid an overdose of the drug contained therein. Said overdose,however, is not the result of a simultaneous administration of aplurality of the dosage forms containing an overall supratherapeuticdose of the drug (multi-tablet dosing), but the result of anacceleration of the release profile and/or the result of the change ofthe route of administration. When accelerating the release profile, e.g.by pulverizing a dosage form, and/or extracting a drug therefrom andadministering the extract, the dose of the drug that was originallycontained in the dosage form is absorbed by the organism in a fastermanner thereby leading to a transient increase of the plasma level. Oncea certain plasma level has been exceeded, an euphoric state can beachieved and this is usually desired by potential abusers. No pluralityof dosage forms is needed in order to achieve such overdose, as a singledosage form already contains a sufficient dose of the drug that—onceabsorbed in a sufficiently fast manner—reaches excessive plasma levels.This type of overdose, i.e. this excessive plasma level, isconventionally prevented by providing dosage forms having an increasedbreaking strength such that they cannot be easily pulverized. Therefore,the type of overdose that is to be conventionally preventedsubstantially differs from the type of overdose that is to be preventedaccording to the invention.

The dosage forms according to the invention can be preferably formulatedto provide an immediate release profile of the pharmacologically activeingredient a as well as of the optionally present pharmacologicallyactive ingredient b, and can also be prepared to include effective oradvantageous abuse deterrent features that are effective to deter abuseof the same (e.g., one that is commonly susceptible to abuse) thatexhibits the immediate release profile. Thus, the dosage forms accordingto the invention combine immediate release with broad abuse resistancefor multiple abuse modalities including multi-tablet dosing. The dosageforms according to the invention can provide an immediate releaseprofile, and can at the same time include abuse deterrent features thatprovide general abuse deterrence or abuse resistance.

The dosage forms can also be more specifically characterized asresistant to certain common methods of abuse, such as 1) abuse byinjection, 2) abuse by nasal insufflation, and 3) abuse by multi-tabletdosing by oral consumption, meaning simultaneous oral ingestion ofmultiple or excessive quantities of orally administered dosage formssuch as tablets or capsules. The third mode of abuse, multi-tabletdosing, is particularly common with immediate release dosage forms andis particularly difficult to defend against by design of a dosage formstructure or by formulation. Accordingly, that the dosage formsaccording to the invention can be effective to prevent or deter abuse(or even accidental overdose) by the mode of multi-tablet dosing is aparticularly useful feature of the dosage forms according to theinvention.

The concept underlying the dosage forms according to the inventionprovides a high degree in flexibility concerning dosage, releaseprofile, tamper-resistance, patient compliance, ease of manufacture andthe like. The dosage forms according to the invention can be preparedfrom a variety of components that are separately prepared. Specificselection of specific components from said variety of components allowsfor tailoring dosage forms satisfying a large variety of differentrequirements. For example, it is possible to make available a variety ofthree different types of particle(s) A that differ e.g. in their contentof pharmacologically active compound a. When manufacturingpharmaceutical dosage forms according to the invention having apredetermined total dosage of pharmacologically active ingredient a, onemay select different combinations of particles A₁, A₂ and A₃ in order toachieve said total dosage of pharmacologically active ingredient a. Forexample, particles A₁ may contain a dosage of 0.25 mg, particles A₂ maycontain a dosage of 1.50 mg, and particles A₃ may contain a dosage of3.50 mg, such that a total dosage of e.g. 5.00 mg pharmacologicallyactive ingredient a can be achieved by

-   -   20 particles A₁;    -   2 particles A₁ in combination with 3 particles A₂;    -   1 particle A₂ in combination with 1 particle A₃; or    -   6 particles A₁ in combination with 1 particle A₃.

Another advantage of the concept underlying the dosage forms accordingto the invention is that nearly every combination may be either filledinto capsules or may be compressed into tablets. This flexibility hasparticular advantages when providing tamper-resistant products that needto satisfy the confidence requirements with respect to the marketingauthorization for the initial non-tamper-resistant product. Thus, thepresent invention makes available at a high degree of flexibilitytamper-resistant counterparts to existent non-tamper-resistant products.If in initial tests the confidence intervals are not met, the presentinvention provides easy and predictable measures for slightly alteringthe properties of the dosage form in order to meet the confidencerequirements.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the preferred behavior of the particle(s) containedin the dosage form according to the invention when being subjected to abreaking strength test, in particular their deformability.

FIG. 2 illustrates the behavior of conventional particle(s) when beingsubjected to a breaking strength test.

FIGS. 3 and 4 show the release profiles of exemplified dosage accordingto the invention that comprise two pharmacologically active ingredients,namely hydrocodone and acetaminophen.

FIG. 3 shows the in vitro release profiles of exemplified dosage formswith respect to the release of hydrocodone (pharmacologically activeingredient a) when testing a single dosage form, a multitude of 5 dosageforms and a multitude of 10 dosage forms expressed in mg of hydrocodonerelease per tablet. FIG. 4 shows the in vitro release profiles ofexemplified dosage forms with respect to the release of acetaminophen(pharmacologically active ingredient b) when testing a single dosageform, a multitude of 5 dosage forms and a multitude of 10 dosage formsexpressed in mg of hydrocodone release per tablet.

FIGS. 5 and 6 illustrate preferred embodiments of pharmaceutical dosageforms according to the invention that comprise two pharmacologicallyactive ingredients a and b.

FIG. 5 illustrates preferred embodiments of pharmaceutical dosage formsaccording to the invention. FIG. 5A illustrates a capsule comprising amultitude of particles A (1) and pharmacologically active ingredient bthat is contained outside the particles A in an outer matrix material,here shown in form of granules (2). Particles A (1) may additionallycomprise a portion b_(A) of pharmacologically active ingredient b and/ora coating comprising a portion b_(C) of pharmacologically activeingredient b. The capsule according to FIG. 5B additionally comprises aportion b_(B) of pharmacologically active ingredient b contained inparticles B (3), whereas the capsule according to FIG. 5C additionallycomprises a portion b_(P) of pharmacologically active ingredient b inform of a powder (4); thus, according to this embodiment, the outermatrix material comprises granules (2) as well as powder (4).

FIG. 6 illustrates the corresponding preferred embodiments of FIG. 5where the dosage form is provided as a tablet comprising an outer matrixmaterial (5) in which particles A (1), the optionally present granules(2), the optionally present particles B (3) and/or the optionallypresent powder are embedded. It is also possible that said outer matrixmaterial (5) consists of granules (2), and the optionally presentparticles B (3) and/or the optionally present powder.

FIG. 7 schematically illustrates the TIMagc system that was used inExamples 2 and 3 (Inventive vs. Comparative).

FIG. 8 illustrates a comparison of the fasted state experimentsaccording to Example 2 for hydrocodone.

FIG. 9 illustrates a comparison of the fed state experiments accordingto Example 2 for hydrocodone.

FIGS. 10A, 10B and 10C illustrate a comparison of fasted versus fedstate experiments for hydrocodone according to Example 2.

FIG. 11 illustrates a comparison of the fasted state experimentsaccording to Example 2 for acetaminophen.

FIG. 12 illustrates a comparison of the fed state experiments accordingto Example 2 for acetaminophen.

FIGS. 13A, 13B and 13C illustrate a comparison of fasted versus fedstate experiments for acetaminophen according to Example 2.

FIG. 14 illustrates a comparison of fasted state experiments foramphetamine (capsules and tablets) according to Example 3.

FIG. 15 illustrates a comparison of fed state experiments foramphetamine (capsules and tablets) according to Example 3.

FIGS. 16A, 16B and 16C illustrate a comparison of fasted versus fedstate experiments for amphetamine (capsules and tablets) according toExample 3.

FIG. 17 illustrates a comparison of fasted state experiments foramphetamine (pellets) according to Example 3.

As used herein, the term “pharmaceutical dosage form” or “dosage form”refers to a pharmaceutical entity comprising a pharmacologically activeingredient a which is actually administered to, or taken by, a patient,preferably orally.

As used herein, expressions such as “tamper resistant”, “abusedeterrent”, “preventing”, “avoiding”, “deterring” or “inhibiting”associated with the abuse and overdose of drugs, relate to features ofthe dosage forms that provide significant physical and chemicalimpediments to these practices and processes. The objective in suchdeterrence includes both making abuse practices significantly moredifficult to carry out, and making any product resulting from an attemptto carry out such abuse practices on the dosage forms significantly lessdesirable, less profitable, and less abusable to the potential abuser.

Preferably, the dosage form according to the invention is a capsule or atablet.

In a preferred embodiment, when the dosage form is a capsule, it ispreferably a sprinkle capsule or a multitude of sprinkle capsules. Thecapsule may comprise the particles and all excipients in form of a loosefilling, i.e. an homogeneous mixture, or in form of layers (layeredcapsule filling).

In another preferred embodiment, when the dosage form is a tablet, thetablet may comprise the particle(s) A in an outer matrix material withhomogeneous distribution or in form of a mantle tablet.

The dosage from comprises particle(s) of a first type, referred to as“particles(s) A” and optionally additional particle(s) of a second type,referred to as “particle(s) B”. The particle(s) A, the optionallypresent particle(s) B, and/or the dosage form as such may befilm-coated.

The dosage form according to the invention comprises one or moreparticles A and optionally, additionally one or more particles B. In thefollowing, it is referred to “particles(s) A” and “particle(s) B” inorder to express that the number of particles in each case may beindependently one or more. When it is referred to “particle(s)”, therespective embodiment independently applies to both, to particle(s) Aand to optionally present particle(s) B.

The dosage form according to the invention may be compressed or moldedin its manufacture, and it may be of almost any size, shape, weight, andcolor. Most dosage forms are intended to be swallowed as a whole andaccordingly, preferred dosage forms according to the invention aredesigned for oral administration. However, alternatively dosage formsmay be dissolved in the mouth, chewed, or dissolved or dispersed inliquid or meal before swallowing, and some may be placed in a bodycavity. Thus, the dosage form according to the invention mayalternatively be adapted for buccal, lingual, rectal or vaginaladministration. Implants are also possible.

In a preferred embodiment, the dosage form according to the inventionpreferably can be regarded as a MUPS formulation (multiple unit pelletsystem). In a preferred embodiment, the dosage form according to theinvention is monolithic. In another preferred embodiment, the dosageform according to the invention is not monolithic. In this regard,monolithic preferably means that the dosage form is formed or composedof material without joints or seams or consists of or constitutes asingle unit.

In a preferred embodiment, the dosage form according to the inventioncontains all ingredients in a dense compact unit which in comparison tocapsules has a comparatively high density. In another preferredembodiment, the dosage form according to the invention contains allingredients in a capsule which in comparison to dense compact unit has acomparatively low density.

An advantage of the dosage forms according to the invention is that uponmanufacture the particle(s) A may be mixed with excipients in differentamounts to thereby produce dosage forms of different strengths. Anotheradvantage of the dosage forms according to the invention is that uponmanufacture the different particle(s) A, i.e. particles A having adifferent constitution, may be mixed with one another to thereby producedosage forms of different properties, e.g. different release rates,different pharmacologically active ingredients a, and the like.

The dosage form according to the invention has preferably a total weightin the range of 0.01 to 1.5 g, more preferably in the range of 0.05 to1.2 g, still more preferably in the range of 0.1 g to 1.0 g, yet morepreferably in the range of 0.2 g to 0.9 g, and most preferably in therange of 0.3 g to 0.8 g.

In a preferred embodiment, the dosage form according to the invention isnot film coated.

In another preferred embodiment, the dosage form according to theinvention is provided, partially or completely, with a conventionalcoating. The dosage forms according to the invention are preferably filmcoated with conventional film coating compositions. Suitable coatingmaterials are commercially available, e.g. under the trademarks Opadry®,Opaglos® and Eudragit®.

The coating can be resistant to gastric juices and dissolve as afunction of the pH value of the release environment. By means of thiscoating, it is possible to ensure that the dosage form according to theinvention passes through the stomach undissolved and the active compoundis only released in the intestines. The coating which is resistant togastric juices preferably dissolves at a pH value of between 5 and 7.5.

The subjects to which the dosage forms according to the invention can beadministered are not particularly limited. Preferably, the subjects areanimals, more preferably human beings.

The tamper-resistant dosage form according to the invention comprisesparticle(s) A which comprise the pharmacologically active ingredient a.Preferably, the particle(s) A contain the total amount ofpharmacologically active ingredient a that is contained in the dosageform according to the invention, i.e. the dosage form according to theinvention preferably does not contain pharmacologically activeingredient a outside particle(s) A.

The particle(s) A contain at least a pharmacologically active ingredienta and a polymer matrix that preferably comprises a polyalkylene oxide.Preferably, however, the particle(s) A contain additional pharmaceuticalexcipients such as disintegrants, antioxidants and plasticizers.

The pharmacologically active ingredient a is embedded, preferablydispersed in a polymer matrix preferably comprising a polyalkyleneoxide. Preferably, the pharmacologically active ingredient a and thepolyalkylene oxide are homogeneously distributed in the core ofparticle(s) A. Thus, the pharmacologically active ingredient a and thepolyalkylene oxide are preferably homogeneously admixed with oneanother. Thus, the particle(s) A according to the invention arepreferably not multilayered, but are preferably composed of ahomogeneous core comprising the pharmacologically active ingredient aand the polyalkylene oxide, which homogenous core may optionally becoated with a film coating material that neither is pH sensitive norcontains the pharmacologically active ingredient a or the polyalkyleneoxide.

The pharmacologically active ingredient a is not particularly limited.

In a preferred embodiment, the particle(s) A and the dosage form,respectively, contain only a single pharmacologically active ingredienta, optionally besides pharmacologically active ingredient b. In anotherpreferred embodiment, the particle(s) A and the dosage form,respectively, contain a combination of two or more pharmacologicallyactive ingredient a, optionally besides pharmacologically activeingredient b.

Preferably, pharmacologically active ingredient a is an activeingredient with potential for being abused. Active ingredients withpotential for being abused are known to the person skilled in the artand comprise e.g. tranquillizers, stimulants, barbiturates, narcotics,opioids or opioid derivatives.

Preferably, the pharmacologically active ingredient a exhibitspsychotropic action, i.e. has a psychotropic effect.

Preferably, the pharmacologically active ingredient a is selected fromthe group consisting of opiates, opioids, stimulants, tranquilizers, andother narcotics.

In a preferred embodiment, the pharmacologically active ingredient a isan opioid. According to the ATC index, opioids are divided into naturalopium alkaloids, phenylpiperi-dine derivatives, diphenylpropylaminederivatives, benzomorphan derivatives, oripavine derivatives, morphinanderivatives and others.

In another preferred embodiment, the pharmacologically active ingredienta is a stimulant. Stimulants are psychoactive drugs that inducetemporary improvements in either mental or physical functions or both.Examples of these kinds of effects may include enhanced wakefulness,locomotion, and alertness. Preferred stimulants are phenylethylaminederivatives. According to the ATC index, stimulants are contained indifferent classes and groups, e.g. psychoanaleptics, especiallypsychostimulants, agents used for ADHD and nootropics, particularlycentrally acting sympathomimetics; and e.g. nasal preparations,especially nasal decongestants for systemic use, particularlysympathomimetics.

The following opiates, opioids, stimulants, tranquillizers or othernarcotics are substances with a psychotropic action, i.e. have apotential of abuse, and hence are preferably contained in the dosageform and the particle(s) A, respectively: alfentanil, allobarbital,allylprodine, alphaprodine, alprazolam, amfepramone, amphetamine,amphetaminil, amobarbital, anileridine, apocodeine, axomadol, barbital,bemidone, benzylmorphine, bezitramide, bromazepam, brotizolam,buprenorphine, butobarbital, butorphanol, camazepam, carfentanil,cathine/D-norpseudoephedrine, cebranopadol, chlordiazepoxide, clobazamclofedanol, clonazepam, clonitazene, clorazepate, clotiazepam,cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine,delorazepam, desomorphine, dex-amphetamine, dextromoramide,dextropropoxyphene, dezocine, diampromide, diamorphone, diazepam,dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol,dimephetamol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone,dronabinol, eptazocine, estazolam, ethoheptazine,ethylmethylthiambutene, ethyl loflazepate, ethylmorphine, etonitazene,etorphine, faxeladol, fencamfamine, fenethylline, fenpipramide,fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam,halazepam, haloxazolam, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, hydroxymethylmorphinan, ketazolam,ketobemidone, levacetylmethadol (LAAM), levomethadone, levorphanol,levophenacyl-morphane, levoxemacin, lisdexamfetamine dimesylate,lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam,mefenorex, meperidine, meprobamate, metapon, meptazinol, metazocine,methylmorphine, metamphetamine, methadone, methaqualone,3-methylfentanyl, 4-methylfentanyl, methylphenidate,methylphenobarbital, methyprylon, metopon, midazolam, modafinil,morphine, myrophine, nabilone, nalbuphene, nalorphine, narceine,nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol,normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam,oxycodone, oxymorphone, Papaver somniferum, papaveretum, pemoline,pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphane,phenazocine, phenoperidine, piminodine, pholcodeine, phenmetrazine,phenobarbital, phentermine, pinazepam, pipradrol, piritramide, prazepam,profadol, proheptazine, promedol, properidine, propoxyphene,pseudoephedrine, remifentanil, secbutabarbital, secobarbital,sufentanil, tapentadol, temazepam, tetrazepam, tilidine (cis and trans),tramadol, triazolam, vinylbital,N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide,(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclo-hexanol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3-(3-dimethyl-amino-1-ethyl-2-methy 1-propyl)phenol,(2R,3R)-1-dimethyl amino-3 (3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,preferably as racemate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)propionate,(RR—SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethyl-aminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR—SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethyl-aminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, andcorresponding stereoisomeric compounds, in each case the correspondingderivatives thereof, physiologically acceptable enantiomers,stereoisomers, diastereomers and racemates and the physiologicallyacceptable derivatives thereof, e.g. ethers, esters or amides, and ineach case the physiologically acceptable compounds thereof, inparticular the acid or base addition salts thereof and solvates, e.g.hydrochlorides.

In a preferred embodiment, the pharmacologically active ingredient a isselected from the group consisting of DPI-125, M6G (CE-04-410),ADL-5859, CR-665, NRP290 and sebacoyl dinalbuphine ester.

In a preferred embodiment, the pharmacologically active ingredient a isan opioid selected from the group consisting of oxycodone, hydrocodone,oxymorphone, hydromorphone, morphine, tramadol, tapentadol, cebranopadoland the physiologically acceptable salts thereof.

In another preferred embodiment, the pharmacologically active ingredienta is a stimulant selected from the group consisting of amphetamine,dex-amphetamine, dex-methylphenidate, atomoxetine, caffeine, ephedrine,phenylpropanolamine, phenylephrine, fencamphamin, fenozolone,fenetylline, methylenedioxymethamphetamine (MDMA),methylenedioxypyrovalerone (MDPV), prolintane, lisdexamfetamine,mephedrone, meth-amphetamine, methylphenidate, modafinil, nicotine,pemoline, phenylpropanolamine, propylhexedrine, dimethylamylamine, andpseudoephedrine.

The pharmacologically active ingredient a may be present in form of aphysiologically acceptable salt, e.g. physiologically acceptable acidaddition salt.

Physiologically acceptable acid addition salts comprise the acidaddition salt forms which can conveniently be obtained by treating thebase form of the active ingredient with appropriate organic andinorganic acids. Active ingredients containing an acidic proton may beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. The termaddition salt also comprises the hydrates and solvent addition formswhich the active ingredients are able to form. Examples of such formsare e.g. hydrates, alcoholates and the like.

The pharmacologically active ingredient a is present in the dosage formin a therapeutically effective amount. The amount that constitutes atherapeutically effective amount varies according to the activeingredients being used, the condition being treated, the severity ofsaid condition, the patient being treated, and the frequency ofadministration.

The content of the pharmacologically active ingredient a in the dosageform is not limited. The dose of the pharmacologically active ingredienta which is adapted for administration preferably is in the range of 0.1mg to 500 mg, more preferably in the range of 1.0 mg to 400 mg, evenmore preferably in the range of 5.0 mg to 300 mg, and most preferably inthe range of 10 mg to 250 mg. In a preferred embodiment, the totalamount of the pharmacologically active ingredient a that is contained inthe dosage form is within the range of from 0.01 to 200 mg, morepreferably 0.1 to 190 mg, still more preferably 1.0 to 180 mg, yet morepreferably 1.5 to 160 mg, most preferably 2.0 to 100 mg and inparticular 2.5 to 80 mg.

The skilled person may readily determine an appropriate amount ofpharmacologically active ingredient a to include in a dosage form. Forinstance, in the case of analgesics, the total amount ofpharmacologically active ingredient a present in the dosage form is thatsufficient to provide analgesia. The total amount of pharmacologicallyactive ingredient a administered to a patient in a dose will varydepending on numerous factors including the nature of thepharmacologically active ingredient a, the weight of the patient, theseverity of the pain, the nature of other therapeutic agents beingadministered etc.

In a particularly preferred embodiment, the pharmacologically activeingredient a is tapentadol, preferably its HCl salt, and the dosage formis adapted for administration once daily, twice daily, thrice daily ormore frequently. In this embodiment, pharmacologically active ingredienta is preferably contained in the dosage form in an amount of from 25 to100 mg.

In a particularly preferred embodiment, the pharmacologically activeingredient a is oxymorphone, preferably its HCl salt, and the dosageform is adapted for administration once daily, twice daily, thrice dailyor more frequently. In this embodiment, the pharmacologically activeingredient a is preferably contained in the dosage form in an amount offrom 5 to 40 mg. In another particularly preferred embodiment, thepharmacologically active ingredient a is oxymorphone, preferably its HClsalt, and the dosage form is adapted for administration once daily. Inthis embodiment, the pharmacologically active ingredient a is preferablycontained in the dosage form in an amount of from 10 to 80 mg.

In another particularly preferred embodiment, the pharmacologicallyactive ingredient a is oxycodone, preferably its HCl salt, and thedosage form is adapted for administration once daily, twice daily,thrice daily or more frequently. In this embodiment, thepharmacologically active ingredient a is preferably contained in thedosage form in an amount of from 5 to 80 mg. Oxycodone, preferably itsHCl salt, is preferably combined with acetaminophen as optionallypresent pharmacologically active ingredient b.

In still another particularly preferred embodiment, thepharmacologically active ingredient a is hydromorphone, preferably itsHCl, and the dosage form is adapted for administration once daily, twicedaily, thrice daily or more frequently. In this embodiment, thepharmacologically active ingredient a is preferably contained in thedosage form in an amount of from 2 to 52 mg. In another particularlypreferred embodiment, the pharmacologically active ingredient a ishydromorphone, preferably its HCl, and the dosage form is adapted foradministration once daily, twice daily, thrice daily or more frequently.In this embodiment, the pharmacologically active ingredient a ispreferably contained in the dosage form in an amount of from 4 to 104mg.

In yet another particularly preferred embodiment, the pharmacologicallyactive ingredient a is hydrocodone, preferably its bitartrate salt, andthe dosage form is adapted for administration once daily, twice daily,thrice daily or more frequently. In this embodiment, thepharmacologically active ingredient a is preferably contained in thedosage form in an amount of from 2.5 to 10 mg. Hydrocodone, preferablyits bitartrate salt, is preferably combined with acetaminophen asoptionally present pharmacologically active ingredient b.

Preferably, the content of the pharmacologically active ingredient a isat least 0.5 wt.-%, based on the total weight of the dosage form and/orbased on the total weight of the particle(s) A.

Preferably, the content of the pharmacologically active ingredient a isat least 2.5 wt.-%, more preferably at least 3.0 wt.-%, still morepreferably at least 3.5 wt.-%, yet more preferably at least 4.0 wt.-%,most preferably at least 4.5 wt.-%, based on the total weight of thedosage form and/or based on the total weight of the particle(s) A.

In a preferred embodiment, the content of the pharmacologically activeingredient a is at most 70 wt.-%, more preferably at most 65 wt.-%,still more preferably at most 60 wt.-%, yet more preferably at most 55wt.-%, most preferably at most 50 wt.-%, based on the total weight ofthe dosage form and/or based on the total weight of the particle(s) A.

In another preferred embodiment, the content of the pharmacologicallyactive ingredient a is at most 20 wt.-%, more preferably at most 17.5wt.-%, still more preferably at most 15 wt.-%, yet more preferably atmost 12.5 wt.-%, most preferably at most 10 wt.-%, based on the totalweight of the dosage form and/or based on the total weight of theparticle(s) A.

Preferably, the content of the pharmacologically active ingredient a iswithin the range of from 0.01 to 80 wt.-%, more preferably 0.1 to 50wt.-%, still more preferably 1 to 25 wt.-%, based on the total weight ofthe dosage form and/or based on the total weight of the particle(s) A.

The particle(s) A present in the dosage forms according to the inventionpreferably comprise 1 to 75 wt.-% of pharmacologically active ingredienta, more preferably 2 to 70 wt.-% of pharmacologically active ingredienta, still more preferably 3 to 65 wt.-% of pharmacologically activeingredient a, based on the total weight of the dosage form and/or basedon the total weight of the particle(s) A.

A skilled person knows how to determine pharmacokinetic parameters suchas t_(1/2), T_(max), C_(max), AUC and bioavailability. For the purposesof the description, the pharmacokinetic parameters, which may bedetermined from the blood plasma concentrations of3-(2-dimethylaminomethylcyclohexyl)phenol, are defined as follows:

C_(max) maximum measured plasma concentration of the active ingredientafter single administration (≡average peak plasma level) t_(max)interval of time from administration of the active ingredient untilC_(max) is reached AUC total area of the plasma concentration/time curveincluding the subarea from the final measured value extrapolated toinfinity t_(1/2) half-life

The above parameters are in each case stated as mean values of theindividual values for all investigated patients/test subjects.

A person skilled in the art knows how the pharmacokinetic parameters ofthe active ingredient may be calculated from the measured concentrationsof the active ingredient in the blood plasma. In this connection,reference may be made, for example, to Willi Cawello (ed.) Parametersfor Compartment-free Pharmacokinetics, Shaker Verlag Aachen (1999).

In a preferred embodiment, the pharmacologically active ingredient a istapentadol or a physiologically acceptable salt thereof, e.g. thehydrochloride. Preferably, the dosage form according to the inventionprovides a mean absolute bioavailability of tapentadol of at least 22%,more preferably at least 24%, still more preferably at least 26%, yetmore preferably at least 28%, most preferably at least 30%, and inparticular at least 32%. T_(max) of tapentadol is preferably within therange of 1.25±1.20 h, more preferably 1.25±1.00 h, still more preferably1.25±0.80 h, yet more preferably 1.25±0.60 h, most preferably 1.25±0.40h, and in particular 1.25±0.20 h. t_(1/2) of tapentadol is preferablywithin the range of 4.0±2.8 h, more preferably 4.0±2.4 h, still morepreferably 4.0±2.0 h, yet more preferably 4.0±1.6 h, most preferably4.0±1.2 h, and in particular 4.0±0.8 h. Preferably, when normalized to adose of 100 mg tapentadol, C_(max) of tapentadol is preferably withinthe range of 90±85 ng/mL, more preferably 90±75 ng/mL, still morepreferably 90±65 ng/mL, yet more preferably 90±55 ng/mL, most preferably90±45 ng/mL, and in particular 90±35 ng/mL; and/or AUC of tapentadol ispreferably within the range of 420±400 ng/mL·h, more preferably 420±350ng/mL·h, still more preferably 420±300 ng/mL·h, yet more preferably420±250 ng/mL·h, most preferably 420±200 ng/mL·h, and in particular420±150 ng/mL·h.

In another preferred embodiment, the pharmacologically active ingredienta is oxycodone or a physiologically acceptable salt thereof, e.g. thehydrochloride. Preferably, the dosage form according to the inventionprovides a mean absolute bioavailability of oxycodone of at least 40%,more preferably at least 45%, still more preferably at least 50%, yetmore preferably at least 55%, most preferably at least 60%, and inparticular at least 70%. T_(max) of oxycodone is preferably within therange of 2.6±2.5 h, more preferably 2.6±2.0 h, still more preferably2.6±1.8 h, yet more preferably 2.6±0.1.6 h, most preferably 2.6±1.4 h,and in particular 2.6±1.2 h. t_(1/2) of oxycodone is preferably withinthe range of 3.8±3.5 h, more preferably 3.8±3.0 h, still more preferably3.8±2.5 h, yet more preferably 3.8±2.0 h, most preferably 3.8±1.5 h, andin particular 3.8±1.0 h. Preferably, when normalized to a dose of 30 mgoxycodone, C_(max) of oxycodone is preferably within the range of 40±35ng/mL, more preferably 40±30 ng/mL, still more preferably 40±25 ng/mL,yet more preferably 40±20 ng/mL, most preferably 40±15 ng/mL, and inparticular 40±10 ng/mL; and/or AUC of oxycodone is preferably within therange of 270±250 ng/mL·h, more preferably 270±200 ng/mL·h, still morepreferably 270±150 ng/mL·h, yet more preferably 270±100 ng/mL·h, mostpreferably 270±75 ng/mL·h, and in particular 270±50 ng/mL·h.

In still another preferred embodiment, the pharmacologically activeingredient a is hydrocodone or a physiologically acceptable saltthereof, e.g. the bitartrate. T_(max) of hydrocodone is preferablywithin the range of 1.3±1.2 h, more preferably 1.3±1.0 h, still morepreferably 1.3±0.8 h, yet more preferably 1.3±0.6 h, most preferably1.3±0.4 h, and in particular 1.3±0.2 h. t_(1/2) of hydrocodone ispreferably within the range of 3.8±3.5 h, more preferably 3.8±3.0 h,still more preferably 3.8±2.5 h, yet more preferably 3.8±2.0 h, mostpreferably 3.8±1.5 h, and in particular 3.8±1.0 h.

In yet another preferred embodiment, the pharmacologically activeingredient a is morphine or a physiologically acceptable salt thereof,e.g. the sulfate. Preferably, the dosage form according to the inventionprovides a mean absolute bioavailability of morphine of at least 15%,more preferably at least 20%, still more preferably at least 25%, yetmore preferably at least 30%, most preferably at least 35%, and inparticular at least 40%. T_(max) of morphine is preferably within therange of 0.625±0.60 h, more preferably 0.625±0.50 h, still morepreferably 0.625±0.40 h, yet more preferably 0.625±0.30 h, mostpreferably 0.625±0.20 h, and in particular 0.625±0.15 h. Preferably,when normalized to a dose of 30 mg morphine sulfate, C_(max) of morphineis preferably within the range of 25±20 ng/mL, more preferably 25±15ng/mL, still more preferably 25±10 ng/mL, yet more preferably 25±5ng/mL; and/or AUC of morphine is preferably within the range of 50±45ng/mL·h, more preferably 50±40 ng/mL·h, still more preferably 50±35ng/mL·h, yet more preferably 50±30 ng/mL·h, most preferably 50±25ng/mL·h, and in particular 50±20 ng/mL·h.

In still another preferred embodiment, the pharmacologically activeingredient a is amphetamine or a physiologically acceptable saltthereof. T_(max) of amphetamine is preferably within the range of1.7±1.2 h, more preferably 1.7±1.0 h, still more preferably 1.7±0.8 h,yet more preferably 1.7±0.6 h, most preferably 1.7±0.4 h, and inparticular 1.7±0.2 h.

In still another preferred embodiment, the pharmacologically activeingredient a is dex-amphetamine or a physiologically acceptable saltthereof, e.g. the sulfate. T_(max) of dex-amphetamine is preferablywithin the range of 3.0±2.9 h, more preferably 3.0±2.5 h, still morepreferably 3.0±2.1 h, yet more preferably 3.0±1.7 h, most preferably3.0±1.3 h, and in particular 3.0±0.9 h. t_(1/2) of dex-amphetamine ispreferably within the range of 10±6.0 h, more preferably 10±5.0 h, stillmore preferably 10±4.0 h, yet more preferably 10±3.0 h, most preferably10±2.0 h, and in particular 10±1.0 h.

In a preferred embodiment, the pharmaceutical dosage form additionallycontains a second pharmacologically active ingredient (pharmacologicallyactive ingredient b).

The optionally present pharmacologically active ingredient b is notparticularly limited. The optionally present pharmacologically activeingredient b differs from the pharmacologically active ingredient a.

In a preferred embodiment, the optionally present pharmacologicallyactive ingredient b exhibits no psychotropic action.

In another preferred embodiment, the optionally presentpharmacologically active ingredient b is selected from ATC classes[M01A], [M01A], [N02B] and [N02C] according to the WHO.

In a particularly preferred embodiment,

-   -   (i) the pharmacologically active ingredient a has a psychotropic        effect; and/or    -   (ii) the optionally present pharmacologically active ingredient        b is selected from ATC classes [M01A], [M01C], [N02B] and [N02C]        according to the WHO.

Preferably, the optionally present pharmacologically active ingredient bis selected from the group consisting of acetylsalicylic acid,aloxiprin, choline salicylate, sodium salicylate, salicylamide,salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate,diflunisal, potassium salicylate, guacetisal, carbasalate calcium,imidazole salicylate, phenazone, metamizole sodium, aminophenazone,propyphenazone, nifenazone, acetaminophen (paracetamol), phenacetin,bucetin, propacetamol, rimazolium, glafenine, floctafenine, viminol,nefopam, flupirtine, ziconotide, methoxyflurane, nabiximols,dihydroergotamine, ergotamine, methysergide, lisuride, flumedroxone,sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan,eletriptan, frovatriptan, pizotifen, clonidine, iprazochrome,dimetotiazine, oxetorone, phenylbutazone, mofebutazone, oxyphenbutazone,clofezone, kebuzone, indomethacin, sulindac, tolmetin, zomepirac,diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac,acemetacin, difenpiramide, oxametacin, proglumetacin, ketorolac,aceclofenac, bufexamac, piroxicam, tenoxicam, droxicam, lornoxicam,meloxicam, ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen,benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen, tiaprofenicacid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen, alminoprofen,dexketoprofen, naproxcinod, mefenamic acid, tolfenamic acid, flufenamicacid, meclofenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib,etoricoxib, lumiracoxib, nabumetone, niflumic acid, azapropazone,glucosamine, benzydamine, glucosaminoglycan polysulfate, proquazone,orgotein, nimesulide, feprazone, diacerein, momiflumate, tenidap,oxaceprol, chondroitin sulfate, oxycinchophen, sodium aurothiomalate,sodium aurotiosulfate, auranofin, aurothioglucose, aurotioprol,penicillamine, bucillamine, their physiologically acceptable salts, aswell as mixtures thereof.

In a preferred embodiment, the optionally present pharmacologicallyactive ingredient b is acetaminophen or ibuprofen, more preferablyacetaminophen.

In a particularly preferred embodiment, the pharmacologically activeingredient a is hydrocodone or a physiologically acceptable salt thereofand the optionally present pharmacologically active ingredient b isacetaminophen.

The optionally present pharmacologically active ingredient b is presentin the dosage form in a therapeutically effective amount. In general,the amount that constitutes a therapeutically effective amount variesaccording to the pharmacologically active ingredients being used, thecondition being treated, the severity of said condition, the patientbeing treated, and whether the dosage form or the segment in which thepharmacologically active ingredient is contained is designed for animmediate or retarded release.

The total amount of the optionally present pharmacologically activeingredient b in the dosage form is not limited. The total amount of theoptionally present pharmacologically active ingredient b which isadapted for administration preferably is in the range of 0.1 mg to 2,000mg or 0.1 mg to 1,000 mg or 0.1 mg to 500 mg, more preferably in therange of 1.0 mg to 400 mg, even more preferably in the range of 5.0 mgto 300 mg, and most preferably in the range of 10 mg to 250 mg. In apreferred embodiment, the total amount of the optionally presentpharmacologically active ingredient b which is contained in the dosageform is within the range of from 10 to 1,000 mg, more preferably 50 to900 mg, still more preferably 100 to 800 mg, yet more preferably 200 to600 mg, most preferably 250 to 500 mg and in particular 300 to 400 mg.In another preferred embodiment, the total amount of the optionallypresent pharmacologically active ingredient b which is contained in thedosage form is within the range of from 10 to 500 mg, more preferably 12to 450 mg, still more preferably 14 to 400 mg, yet more preferably 16 to375 mg, most preferably 18 to 350 mg and in particular 20 to 325 mg.

The total content of the optionally present pharmacologically activeingredient b preferably ranges from about 0.01 wt.-% to about 95 wt.-%,more preferably from about 0.1 wt.-% to about 80 wt.-%, even morepreferably from about 1.0 wt.-% to about 50 wt.-%, yet more preferablyfrom about 1.5 wt.-% to about 30 wt.-%, and most preferably from about2.0 wt.-% to 20 wt.-%, based on the total weight of the dosage form.

Preferably, the total content of the optionally presentpharmacologically active ingredient b is within the range of from 0.01to 80 wt.-%, more preferably 0.1 to 50 wt.-%, still more preferably 1 to25 wt.-%, based on the total weight of the dosage form.

In a particularly preferred embodiment, the optionally presentpharmacologically active ingredient b is acetaminophen. In thisembodiment, the acetaminophen is preferably contained in the particle(s)B or the dosage form in an amount of from 100 to 600 mg, more preferably150 to 550 mg, still more preferably 200 to 500 mg, most preferably 250to 450 mg and in particular 275 to 400 mg.

In another particularly preferred embodiment, the optionally presentpharmacologically active ingredient b is ibuprofen. In this embodiment,the ibuprofen is preferably contained in the particle(s) B or the dosageform in an amount of from 100 to 600 mg, more preferably 150 to 550 mg,still more preferably 200 to 500 mg, most preferably 250 to 450 mg andin particular 275 to 400 mg.

Preferred combinations A¹ to A³⁶ of the pharmacologically activeingredient a and the optionally present pharmacologically activeingredient b are summarized in the table here below, wherein thepharmacologically active ingredient a as well as the optionally presentpharmacologically active ingredient b each also refer to thephysiologically acceptable salts thereof, particularly to thehydrochlorides or bitartrates:

a b a b A¹ oxycodone ibuprofen A¹⁰ oxycodone acetaminophen A²oxymorphone ibuprofen A¹¹ oxymorphone acetaminophen A³ hydrocodoneibuprofen A¹² hydrocodone acetaminophen A⁴ hydromorphone ibuprofen A¹³hydromorphone acetaminophen A⁵ morphine ibuprofen A¹⁴ morphineacetaminophen A⁶ tapentadol ibuprofen A¹⁵ tapentadol acetaminophen A⁷tramadol ibuprofen A¹⁶ tramadol acetaminophen A⁸ buprenorphine ibuprofenA¹⁷ buprenorphine acetaminophen A⁹ pseudoephedrine ibuprofen A¹⁸pseudoephedrine acetaminophen A¹⁹ oxycodone diclofenac A²⁸ oxycodoneacetylsalicylic acid A²⁰ oxymorphone diclofenac A²⁹ oxymorphoneacetylsalicylic acid A²¹ hydrocodone diclofenac A³⁰ hydrocodoneacetylsalicylic acid A²² hydromorphone diclofenac A³¹ hydromorphoneacetylsalicylic acid A²³ morphine diclofenac A³² morphineacetylsalicylic acid A²⁴ tapentadol diclofenac A³³ tapentadolacetylsalicylic acid A²⁵ tramadol diclofenac A³⁴ tramadolacetylsalicylic acid A²⁶ buprenorphine diclofenac A³⁵ buprenorphineacetylsalicylic acid A²⁷ pseudoephedrine diclofenac A³⁶ pseudoephedrineacetylsalicylic acid

In a preferred embodiment, the relative weight ratio of the totalcontent of the pharmacologically active ingredient a to the totalcontent of the optionally present pharmacologically active ingredient b[a:b] is within the range of (8±1):1, more preferably (7±1):1, stillmore preferably (6±1):1, yet more preferably (5±1):1, even morepreferably (4±1):1, most preferably (3±1):1 and in particular (2±1):1.

In still another preferred embodiment, the relative weight ratio of thetotal content of the optionally present pharmacologically activeingredient b to the total content of the pharmacologically activeingredient a [b:a] is within the range of (8±1):1, more preferably(7±1):1, still more preferably (6±1):1, yet more preferably (5±1):1,even more preferably (4±1):1, most preferably (3±1):1 and in particular(2±1):1. Preferably, the relative weight ratio of the total content ofthe optionally present pharmacologically active ingredient b to thetotal content of the pharmacologically active ingredient a [b:a] iswithin the range of from 10:1 to 150:1, more preferably 10:1 to 50:1, or30:1 to 140:1.

The dosage form according to the invention preferably provides fastrelease, more preferably immediate release under in vitro conditions ofthe pharmacologically active ingredient a, and independently of theoptionally present pharmacologically active ingredient b in accordancewith Ph. Eur.

The term “immediate release” as applied to dosage forms is understood bypersons skilled in the art which has structural implications for therespective dosage forms. The term is defined, for example, in thecurrent issue of the US Pharmacopoeia (USP), General Chapter 1092, “THEDISSOLUTION PROCEDURE: DEVELOPMENT AND VALIDATION”, heading “STUDYDESIGN”, “Time Points”. For immediate-release dosage forms, the durationof the procedure is typically 30 to 60 minutes; in most cases, a singletime point specification is adequate for Pharmacopeia purposes.Industrial and regulatory concepts of product comparability andperformance may require additional time points, which may also berequired for product registration or approval. A sufficient number oftime points should be selected to adequately characterize the ascendingand plateau phases of the dissolution curve. According to theBiopharmaceutics Classification System referred to in several FDAGuidances, highly soluble, highly permeable drugs formulated withrapidly dissolving products need not be subjected to a profilecomparison if they can be shown to release 85% or more of the activedrug substance within 15 minutes. For these types of products aone-point test will suffice. However, most products do not fall intothis category. Dissolution profiles of immediate-release productstypically show a gradual increase reaching 85% to 100% at 30 to 45minutes. Thus, dissolution time points in the range of 15, 20, 30, 45,and 60 minutes are usual for most immediate-release products.

Preferably, the dosage form according to the invention provides an invitro release profile of the pharmacologically active ingredient a suchthat after 30 min under in vitro conditions at 37° C. in 900 mL 0.1 MHCl at 25 rpm in accordance with Ph. Eur.

-   (i) a single dosage form has released at least 30 wt.-%, or at least    31 wt.-%, or at least 32 wt.-%, or at least 33 wt.-%, or at least 34    wt.-%, or at least 35 wt.-%, or at least 36 wt.-%, or at least 37    wt.-%, or at least 38 wt.-%, or at least 39 wt.-%, or at least 40    wt.-%, of the pharmacologically active ingredient a originally    contained in the dosage form; and/or-   (ii) a multitude of ten dosage forms has released not more than 25    wt.-%, or not more than 24 wt.-%, or not more than 23 wt.-%, or not    more than 22 wt.-%, or not more than 21 wt.-%, or not more than 20    wt.-%, or not more than 19 wt.-%, or not more than 18 wt.-%, or not    more than 17 wt.-%, or not more than 16 wt.-%, or not more than 15    wt.-%, of the overall content of the pharmacologically active    ingredient a originally contained in the multitude of ten dosage    forms.

Preferably, the dosage form according to the invention provides an invitro release profile of the pharmacologically active ingredient a suchthat after 30 min under in vitro conditions at 37° C. in 900 mL 0.1 MHCl at 25 rpm in accordance with Ph. Eur.

-   (i) a single dosage form has released X mg of the pharmacologically    active ingredient a originally contained in the dosage form; and-   (ii) a multitude of n dosage forms has released Y mg of the    pharmacologically active ingredient a originally contained in the a    multitude of n dosage forms;    wherein Y/n is not more than 50% of X, preferably not more than 45%    of X, still more preferably not more than 40% of X, yet more    preferably not more than 35% of X, most preferably not more than 30%    of X; and wherein n is an integer of from 2 to 10, preferably 5 or    10, more preferably 10.

For example, when a single dosage form has released after 30 minutes4.65 mg of pharmacologically active ingredient a, X is 4.65. Under thesecircumstances, a multitude of 10 dosage forms (n=10) must not releasemore than a total of 23.25 mg of the pharmacologically active ingredienta.

Preferably, when the dosage form according to the invention comprisesthe optionally present pharmacologically active ingredient b, the dosageform provides an in vitro release profile of the pharmacologicallyactive ingredient b such that after 30 min under in vitro conditions at37° C. in 900 mL 0.1 M HCl at 25 rpm in accordance with Ph. Eur.

-   (i) a single dosage form has released V mg of the pharmacologically    active ingredient b originally contained in the dosage form; and-   (ii) a multitude of n dosage forms has released W mg of the    pharmacologically active ingredient b originally contained in the a    multitude of n dosage forms;    wherein W/n is not more than 50% of V, preferably not more than 45%    of V, still more preferably not more than 40% of V, yet more    preferably not more than 35% of V, most preferably not more than 30%    of V; and wherein n is an integer of from 2 to 10, preferably 5 or    10, more preferably 10.

Suitable in vitro conditions are known to the skilled artisan. In thisregard it can be referred to, e.g., the Eur. Ph. Preferably, the releaseprofile is measured under the following conditions: Paddle apparatusequipped without sinker, 25 rpm, 37±5° C., 900 mL 0.1 N HCl.

Further preferred release profiles B¹ to B¹⁰ that independently apply tothe release of pharmacologically active ingredient a and optionallypresent pharmacologically active ingredient b are summarized in thetable here below [all data in wt.-% of released pharmacologically activeingredient a/b]:

time B¹ B² B³ B⁴ B⁵ B⁶ B⁷ B⁸ B⁹ B¹⁰ 10 min ≥30 ≥35 ≥40 ≥45 ≥50 ≥60 ≥70≥80 ≥80 ≥80 20 min ≥50 ≥55 ≥60 ≥65 ≥70 ≥75 ≥80 ≥85 ≥90 ≥95 30 min ≥55≥60 ≥65 ≥70 ≥75 ≥85 ≥90 ≥95 ≥95 ≥95 40 min ≥60 ≥65 ≥70 ≥80 ≥85 ≥90 ≥95≥95 ≥95 ≥95 50 min ≥65 ≥70 ≥80 ≥85 ≥88 ≥92 ≥95 ≥95 ≥95 ≥95 60 min ≥75≥80 ≥85 ≥90 ≥92 ≥94 ≥95 ≥95 ≥95 ≥95

In a preferred embodiment, the dosage form according to the invention isadapted for administration once daily. In another preferred embodiment,the dosage form according to the invention is adapted for administrationtwice daily. In still another preferred embodiment, the dosage formaccording to the invention is adapted for administration thrice daily.In yet another preferred embodiment, the dosage form according to theinvention is adapted for administration more frequently than thricedaily, for example 4 times daily, 5 times daily, 6 times daily, 7 timesdaily or 8 times daily.

Preferably, the dosage form according to the invention has under invitro conditions a disintegration time measured in accordance with Ph.Eur. of at most 10 minutes, more preferably at most 8 minutes, or atmost 6 minutes, or at most 5 minutes, more preferably at most 4 minutes,still more preferably at most 3 minutes, yet more preferably at most 2.5minutes, most preferably at most 2 minutes and in particular at most 1.5minutes.

The dosage form according to the invention comprises one or moreparticle(s) A, typically a multitude of particles A. The particle(s) Acomprise a pharmacologically active ingredient a, which is embedded in apolymer matrix that preferably comprises a polyalkylene oxide andpreferably further excipients.

For the purpose of the specification, the term “particle” refers to adiscrete mass of material that is solid, e.g. at 20° C. or at roomtemperature or ambient temperature. Preferably a particle is solid at20° C. Preferably, the individual particle(s) A are monoliths. Themultitude of particles A, however, is not monolithic, butmultiparticulate. Preferably, the pharmacologically active ingredient aand the constituents of the polymer matrix are intimately homogeneouslydistributed in the particle(s) A so that the particle(s) A do notcontain any segments where either pharmacologically active ingredient ais present in the absence of polymer matrix or where polymer matrix ispresent in the absence of pharmacologically active ingredient a.

It is principally possible that the dosage form according to theinvention comprises a single particle A.

In another preferred embodiment, the dosage form according to theinvention comprises a plurality of particles A, more preferably amultitude of particles A.

In a preferred embodiment, the dosage form comprises at least 2, or atleast 3, or at least 4, or at least 5 particles A. Preferably, thedosage form comprises not more than 10, or not more than 9, or not morethan 8, or not more than 7 particles A.

In another preferred embodiment, the particles A amount to a totalnumber within the range of from 20 to 600. More preferably, the dosageform comprises at least 30, or at least 60, or at least 90, or at least120, or at least 150 particles A. Preferably, the dosage form comprisesnot more than 500, or not more than 400, or not more than 300, or notmore than 200 particles A.

Preferably, when the dosage form contains more than a single particle A,the individual particles A may be of the same or of different size,shape and/or composition.

In a preferred embodiment, all particles A are made from the samemixture of ingredients and/or are substantially of the same size, shape,weight and composition.

In another preferred embodiment, particles A can be divided into atleast 2 or at least 3 different types, e.g. particles A₁, particles A₂,and optionally particles A₃, that differ from one another in at leastone property, preferably being selected from the group consisting ofsize, shape, weight, composition, release profile, breaking strength andresistance against solvent extraction.

The content of the particle(s) is not particularly limited andpreferably amounts to a total content within the range of from 10 wt.-%to 80 wt.-%, based on the total weight of the dosage form. Preferably,the content of the particle(s) A in the dosage forms according to theinvention is at most 99 wt.-%, or at most 98 wt.-%, or at most 96 wt.-%,or at most 94 wt.-%, more preferably at most 92 wt.-%, or at most 90wt.-%, or at most 88 wt.-%, or at most 86 wt.-%, still more preferablyat most 84 wt.-%, or at most 82 wt.-%, or at most 80 wt.-%, or at most78 wt.-%, yet more preferably at most 76 wt.-%, or at most 74 wt.-%, orat most 72 wt.-%, or at most 70 wt.-%, most preferably at most 65 wt.-%,or at most 60 wt.-%, or at most 55 wt.-%, or at most 50 wt.-%, and inparticular at most 45 wt.-%, or at most 40 wt.-%, or at most 35 wt.-%,or at most 30 wt.-%, based on the total weight of the dosage form.

Preferably, the content of the particle(s) A in the dosage formsaccording to the invention is at least 2.5 wt.-%, at least 3.0 wt.-%, atleast 3.5 wt.-% or at least 4.0 wt.-%; more preferably at least 4.5wt.-%, at least 5.0 wt.-%, at least 5.5 wt.-% or at least 6.0 wt.-%;still more preferably at least 6.5 wt.-%, at least 7.0 wt.-%, at least7.5 wt.-% or at least 8.0 wt.-%; yet more preferably at least 8.5 wt.-%,at least 9.0 wt.-%, at least 9.5 wt.-% or at least 10 wt.-%; even morepreferably at least 11 wt.-%, at least 12 wt.-%, at least 13 wt.-% or atleast 14 wt.-%; most preferably at least 15 wt.-%, at least 17.5 wt.-%,at least 20 wt.-% or at least 22.5 wt.-%; and in particular at least 25wt.-%, at least 27.5 wt.-%, at least 30 wt.-% or at least 35 wt.-%;based on the total weight of the dosage form.

In a preferred embodiment, the dosage form according to the inventioncomprises one or more particle(s) A comprising a pharmacologicallyactive ingredient a as well as one or more particle(s) B comprising anoptionally present pharmacologically active ingredient b. As besides thedifferent pharmacologically active ingredient a and b, respectively, theparticle(s) A and the particle(s) B have preferably, but independentlyof one another corresponding composition and properties, in thefollowing it is referred to “particle(s)” meaning that these preferredembodiments independently apply to particle(s) A as well as tooptionally present particle(s) B.

When the particle(s) are film coated, the polymer matrix is preferablyhomogeneously distributed in the core of the dosage form, i.e. the filmcoating preferably does not contain polymer matrix. Nonetheless, thefilm coating as such may of course contain one or more polymers, whichhowever, preferably differ from the constituents of the polymer matrixcontained in the core.

When the particle(s) are film coated, the pharmacologically activeingredient a/b is preferably homogeneously distributed in the core ofthe dosage form, i.e. the film coating preferably does not containpharmacologically active ingredient a/b.

The shape of the particle(s) is not particularly limited. As theparticle(s) are preferably manufactured by hot-melt extrusion, preferredparticle(s) present in the dosage forms according to the invention aregenerally cylindrical in shape. The diameter of such particle(s) istherefore the diameter of their circular cross section. The cylindricalshape is caused by the extrusion process according to which the diameterof the circular cross section is a function of the extrusion die and thelength of the cylinders is a function of the cutting length according towhich the extruded strand of material is cut into pieces of preferablymore or less predetermined length.

The suitability of cylindrical, i.e. a spherical particle(s) for themanufacture of the dosage forms according to the invention isunexpected. Typically, the aspect ratio is regarded as an importantmeasure of the spherical shape. The aspect ratio is defined as the ratioof the maximal diameter (d_(max)) and its orthogonal Feret-diameter. Foraspherical particle(s), the aspect ratio has values above 1. The smallerthe value the more spherical is the particle(s). Aspect ratios below 1.1are typically considered satisfactory, aspect ratios above 1.2, however,are typically considered not suitable for the manufacture ofconventional dosage forms. The inventors have surprisingly found thatwhen manufacturing the dosage forms according to the invention, evenparticle(s) having aspect ratios above 1.2 can be processed withoutdifficulties and that it is not necessary to provide sphericalparticle(s). In a preferred embodiment, the aspect ratio of theparticle(s) is at most 1.40, more preferably at most 1.35, still morepreferably at most 1.30, yet more preferably at most 1.25, even morepreferably at most 1.20, most preferably at most 1.15 and in particularat most 1.10. In another preferred embodiment, the aspect ratio of theparticle(s) is at least 1.10, more preferably at least 1.15, still morepreferably at least 1.20, yet more preferably at least 1.25, even morepreferably at least 1.30, most preferably at least 1.35 and inparticular at least 1.40.

The particle(s) are of macroscopic size, typically the average diameteris within the range of from 100 μm to 1500 μm, preferably 200 μm to 1500μm, more preferably 300 μm to 1500 μm, still more preferably 400 μm to1500 μm, most preferably 500 μm to 1500 μm, and in particular 600 μm to1500 μm.

The particle(s) in the dosage forms according to the invention are ofmacroscopic size, i.e. typically have an average particle(s) size of atleast 50 μm, more preferably at least 100 μm, still more preferably atleast 150 μm or at least 200 μm, yet more preferably at least 250 μm orat least 300 μm, most preferably at least 400 μm or at least 500 μm, andin particular at least 550 μm or at least 600 μm.

Preferred particle(s) have an average length and average diameter of1000 μm or less. When the particle(s) are manufactured by extrusiontechnology, the “length” of particle(s) is the dimension of theparticle(s) that is parallel to the direction of extrusion. The“diameter” of particle(s) is the largest dimension that is perpendicularto the direction of extrusion.

Particularly preferred particle(s) have an average diameter of less than1000 μm, more preferably less than 800 μm, still more preferably of lessthan 650 μm. Especially preferred particle(s) have an average diameterof less than 700 μm, particularly less than 600 μm, still moreparticularly less than 500 μm, e.g. less than 400 μm. Particularlypreferred particle(s) have an average diameter in the range 200 to 1000μm, more preferably 400 to 800 μm, still more preferably 450 to 700 μm,yet more preferably 500 to 650 μm, e.g. 500 to 600 μm. Further preferredparticle(s) have an average diameter of between 300 μm and 400 μm, ofbetween 400 μm and 500 μm, or of between 500 μm and 600 μm, or ofbetween 600 μm and 700 μm or of between 700 μm and 800 μm.

Preferred particle(s) that are present in the dosage forms according tothe invention have an average length of less than 1000 μm, preferably anaverage length of less than 800 μm, still more preferably an averagelength of less than 650 μm, e.g. a length of 800 μm, 700 μm 600 μm, 500μm, 400 μm or 300 μm. Especially preferred particle(s) have an averagelength of less than 700 μm, particularly less than 650 μm, still moreparticularly less than 550 μm, e.g. less than 450 μm. Particularlypreferred particle(s) therefore have an average length in the range200-1000 μm, more preferably 400-800 μm, still more preferably 450-700μm, yet more preferably 500-650 μm, e.g. 500-600 μm. The minimum averagelength of the microparticle(s) is determined by the cutting step and maybe, e.g. 500 μm, 400 μm, 300 μm or 200 μm.

In a preferred embodiment, the particle(s) have (i) an average diameterof 1000±300 μm, more preferably 1000±250 μm, still more preferably1000±200 μm, yet more preferably 1000±150 μm, most preferably 1000±100μm, and in particular 1000±50 μm; and/or (ii) an average length of1000±300 μm, more preferably 1000±250 μm, still more preferably 1000±200μm, yet more preferably 1000±150 μm, most preferably 1000±100 μm, and inparticular 1000±50 μm.

The size of particle(s) may be determined by any conventional procedureknown in the art, e.g. laser light scattering, sieve analysis, lightmicroscopy or image analysis.

Preferably, the individual particle(s) have a weight within the range offrom 0.1 mg to 5.0 mg.

In preferred embodiments, the individual particle(s) preferably have aweight within the range of 1.0±0.9 mg, or 1.0±0.8 mg, or 1.0±0.7 mg, or1.0±0.6 mg, or 1.0±0.5 mg, or 1.0±0.4 mg, or 1.0±0.3 mg; or 1.5±0.9 mg,or 1.5±0.8 mg, or 1.5±0.7 mg, or 1.5±0.6 mg, or 1.5±0.5 mg, or 1.5±0.4mg, or 1.5±0.3 mg; or 2.0±0.9 mg, or 2.0±0.8 mg, or 2.0±0.7 mg, or2.0±0.6 mg, or 2.0±0.5 mg, or 2.0±0.4 mg, or 2.0±0.3 mg; or 2.5±0.9 mg,or 2.5±0.8 mg, or 2.5±0.7 mg, or 2.5±0.6 mg, or 2.5±0.5 mg, or 2.5±0.4mg, or 2.5±0.3 mg; or 3.0±0.9 mg, or 3.0±0.8 mg, or 3.0±0.7 mg, or3.0±0.6 mg, or 3.0±0.5 mg, or 3.0±0.4 mg, or 3.0±0.3 mg.

Preferably, the particle(s) A have a total weight over all particles Awithin the range of from 10 mg to 500 mg. In preferred embodiments, thetotal weight of the particle(s) A is within the range of 180±170 mg, or180±150 mg, or 180±130 mg, or 180±110 mg, or 180±90 mg, or 180±70 mg, or180±50 mg, or 180±30 mg.

Preferably, the particle(s) that are contained in the dosage formaccording to the invention have an arithmetic average weight, in thefollowing referred to as “aaw”, wherein at least 70%, more preferably atleast 75%, still more preferably at least 80%, yet more preferably atleast 85%, most preferably at least 90% and in particular at least 95%of the individual particle(s) contained in said one or more particle(s)has an individual weight within the range of aaw±30%, more preferablyaaw±25%, still more preferably aaw±20%, yet more preferably aaw±15%,most preferably aaw±10%, and in particular aaw±5%. For example, if thedosage form according to the invention contains a plurality of 100particles and aaw of said plurality of particles is 1.00 mg, at least 75individual particles (i.e. 75%) have an individual weight within therange of from 0.70 to 1.30 mg (1.00 mg±30%).

In a preferred embodiment, the particle(s) are not film coated. Inanother preferred embodiment, the particle(s) are film coated.

The particle(s) according to the invention can optionally be provided,partially or completely, with a conventional coating. The particle(s)according to the invention are preferably film coated with conventionalfilm coating compositions. Suitable coating materials are commerciallyavailable, e.g. under the trademarks Opadry® and Eudragit®.

When the particle(s) are film coated, the content of the dried filmcoating is preferably at most 5 wt.-%, more preferably at most 4 wt.-%,still more preferably at most 3.5 wt.-%, yet more preferably at most 3wt.-%, most preferably at most 2.5 wt.-%, and in particular at most 2wt.-%, based on the total weight of the particle(s). In a particularlypreferred embodiment, the weight increase based on the total weight ofthe dosage form and/or based on the total weight of the particle(s)(uncoated starting material) is within the range of from 3.0 to 4.7wt.-%, more preferably 3.1 to 4.6 wt.-%, still more preferably 3.2 to4.5 wt.-%, yet more preferably 3.3 to 4.4 wt.-%, most preferably 3.4 to4.3 wt.-%, and in particular 3.5 to 4.2 wt.-%.

In a preferred embodiment of the invention, the film coating of theparticle(s) A contains the total amount of the optionally presentpharmacologically active ingredient b or a portion b_(C) thereof.

The tamper-resistant dosage form according to the invention comprisesone or more particle(s) A which comprise a polymer matrix, wherein thepolymer matrix preferably comprises a polyalkylene oxide, preferably ata content of at least 25 wt.-%, based on the total weight of the dosageform and/or based on the total weight of the particle(s) A. Theoptionally present particle(s) B may also, independently of theparticle(s) A, comprise a polymer matrix, wherein the polymer matrixpreferably comprises a polyalkylene oxide, preferably at a content of atleast 25 wt.-%, based on the total weight of the dosage form and/orbased on the total weight of the particle(s) B.

Preferably, the polyalkylene oxide is selected from polymethylene oxide,polyethylene oxide and polypropylene oxide, or copolymers thereof.Polyethylene oxide is preferred.

Preferably, the polyalkylene oxide has a weight average molecular weightof at least 200,000 g/mol, more preferably at least 500,000 g/mol. In apreferred embodiment, the polyalkylene oxide has a weight averagemolecular weight (M_(W)) or viscosity average molecular weight (M_(η))of at least 750,000 g/mol, preferably at least 1,000,000 g/mol or atleast 2,500,000 g/mol, more preferably in the range of 1,000,000 g/molto 15,000,000 g/mol, and most preferably in the range of 5,000,000 g/molto 10,000,000 g/mol. Suitable methods to determine M_(W) and M_(η) areknown to a person skilled in the art. M_(η) is preferably determined byrheological measurements, whereas M_(w) can be determined by gelpermeation chromatography (GPC).

Polyalkylene oxide may comprise a single polyalkylene oxide having aparticular average molecular weight, or a mixture (blend) of differentpolymers, such as two, three, four or five polymers, e.g., polymers ofthe same chemical nature but different average molecular weight,polymers of different chemical nature but same average molecular weight,or polymers of different chemical nature as well as different molecularweight.

For the purpose of the specification, a polyalkylene glycol has amolecular weight of up to 20,000 g/mol whereas a polyalkylene oxide hasa molecular weight of more than 20,000 g/mol. In a preferred embodiment,the weight average over all molecular weights of all polyalkylene oxidesthat are contained in the dosage form is at least 200,000 g/mol. Thus,polyalkylene glycols, if any, are preferably not taken intoconsideration when determining the weight average molecular weight ofpolyalkylene oxide.

The polyalkylene oxide may be combined with one or more differentpolymers selected from the group consisting of polyalkylene oxide,preferably polymethylene oxide, polyethylene oxide, polypropylene oxide;polyethylene, polypropylene, polyvinyl chloride, polycarbonate,polystyrene, polyvinylpyrrolidone, poly(alk)acrylate, poly(hydroxy fattyacids), such as for example poly(3-hydroxybutyrate-co-3-hydroxyvalerate)(Biopol®), poly(hydroxyvaleric acid); polycaprolactone, polyvinylalcohol, polyesteramide, polyethylene succinate, polylactone,polyglycolide, polyurethane, polyamide, polylactide, polyacetal (forexample polysaccharides optionally with modified side chains),polylactide/glycolide, polylactone, polyglycolide, polyorthoester,polyanhydride, block polymers of polyethylene glycol and polybutyleneterephthalate (Polyactive®), polyanhydride (Polifeprosan), copolymersthereof, block-copolymers thereof (e.g., Poloxamer®), and mixtures of atleast two of the stated polymers, or other polymers with the abovecharacteristics.

Preferably, the molecular weight dispersity M_(w)/M_(n) of polyalkyleneoxide is within the range of 2.5±2.0, more preferably 2.5±1.5, stillmore preferably 2.5±1.0, yet more preferably 2.5±0.8, most preferably2.5±0.6, and in particular 2.5±0.4.

The polyalkylene oxide preferably has a viscosity at 25° C. of 30 to17,600 cP, more preferably 55 to 17,600 cP, still more preferably 600 to17,600 cP and most preferably 4,500 to 17,600 cP, measured in a 5 wt.-%aqueous solution using a model RVF Brookfield viscosimeter (spindle no.2/rotational speed 2 rpm); of 400 to 4,000 cP, more preferably 400 to800 cP or 2,000 to 4,000 cP, measured on a 2 wt.-% aqueous solutionusing the stated viscosimeter (spindle no. 1 or 3/rotational speed 10rpm); or of 1,650 to 10,000 cP, more preferably 1,650 to 5,500 cP, 5,500to 7,500 cP or 7,500 to 10,000 cP, measured on a 1 wt.-% aqueoussolution using the stated viscosimeter (spindle no. 2/rotational speed 2rpm).

Polyethylene oxide that is suitable for use in the dosage formsaccording to the invention is commercially available from Dow. Forexample, Polyox WSR N-12K, Polyox N-60K, Polyox WSR 301 NF or Polyox WSR303NF may be used in the dosage forms according to the invention. Fordetails concerning the properties of these products, it can be referredto e.g. the product specification.

Preferably, the content of the polyalkylene oxide is within the range offrom 25 to 80 wt.-%, more preferably 25 to 75 wt.-%, still morepreferably 25 to 70 wt.-%, yet more preferably 25 to 65 wt.-%, mostpreferably 30 to 65 wt.-% and in particular 35 to 65 wt.-%, based on thetotal weight of the dosage form and/or based on the total weight of theparticle(s). In a preferred embodiment, the content of the polyalkyleneoxide is at least 30 wt.-%, more preferably at least 35 wt.-%, stillmore preferably at least 40 wt.-%, yet more preferably at least 45 wt.-%and in particular at least 50 wt.-%, based on the total weight of thedosage form and/or based on the total weight of the particle(s).

In a preferred embodiment, the overall content of polyalkylene oxide iswithin the range of 35±8 wt.-%, more preferably 35±6 wt.-%, mostpreferably 35±4 wt.-%, and in particular 35±2 wt.-%, based on the totalweight of the dosage form and/or based on the total weight of theparticle(s). In another preferred embodiment, the overall content ofpolyalkylene oxide is within the range of 40±12 wt.-%, more preferably40±10 wt.-%, most preferably 40±7 wt.-%, and in particular 40±3 wt.-%,based on the total weight of the dosage form and/or based on the totalweight of the particle(s). In still another preferred embodiment, theoverall content of polyalkylene oxide is within the range of 45±16wt.-%, more preferably 45±12 wt.-%, most preferably 45±8 wt.-%, and inparticular 45±4 wt.-%, based on the total weight of the dosage formand/or based on the total weight of the particle(s). In yet anotherpreferred embodiment, the overall content of polyalkylene oxide iswithin the range of 50±20 wt.-%, more preferably 50±15 wt.-%, mostpreferably 50±10 wt.-%, and in particular 50±5 wt.-%, based on the totalweight of the dosage form and/or based on the total weight of theparticle(s). In a further preferred embodiment, the overall content ofpolyalkylene oxide is within the range of 55±20 wt.-%, more preferably55±15 wt.-%, most preferably 55±10 wt.-%, and in particular 55±5 wt.-%,based on the total weight of the dosage form and/or based on the totalweight of the particle(s). In still a further a preferred embodiment,the overall content of polyalkylene oxide is within the range of 60±20wt.-%, more preferably 60±15 wt.-%, most preferably 60±10 wt.-%, and inparticular 60±5 wt.-%. In a still further a preferred embodiment, theoverall content of polyalkylene oxide is within the range of 65±20wt.-%, more preferably 65±15 wt.-%, and most preferably 65±10 wt.-%, andin particular 65±5 wt.-%, based on the total weight of the dosage formand/or based on the total weight of the particle(s).

Preferably, the relative weight ratio of the polyalkylene oxide to thepharmacologically active ingredient a is within the range of 30:1 to1:10, more preferably 20:1 to 1:1, still more preferably 15:1 to 5:1,yet more preferably 14:1 to 6:1, most preferably 13:1 to 7:1, and inparticular 12:1 to 8:1.

Preferably, the total content of the polyalkylene oxide in thepharmaceutical dosage form according to the invention amounts to atleast 25 mg, or at least 30 mg, or at least 35 mg, or at least 40 mg, orat least 45 mg; more preferably at least 50 mg, or at least 55 mg, or atleast 60 mg, or at least 65 mg, or at least 70 mg, or at least 75 mg;still more preferably at least 80 mg, or at least 85 mg, or at least 90mg, or at least 95 mg; and most preferably at least 100 mg.

The dosage form according to the invention is preferablytamper-resistant.

As used herein, the term “tamper-resistant” refers to dosage forms thatare preferably resistant to conversion into a form suitable for misuseor abuse, particular for nasal and/or intravenous administration, byconventional means such as grinding in a mortar or crushing by means ofa hammer. In this regard, the dosage forms as such may be crushable byconventional means. However, the particle(s) A contained in the dosageforms according to the invention preferably exhibit mechanicalproperties such that they cannot be pulverized by conventional means anyfurther. The same may independently apply to the optionally presentparticle(s) B. As the particle(s) A are of macroscopic size and containthe pharmacologically active ingredient a, and as the optionally presentparticle(s) B may independently be of macroscopic size and contain theoptionally present pharmacologically active ingredient b, they cannot beadministered nasally thereby rendering the dosage formstamper-resistant.

Preferably, the particle(s) A have a breaking strength of at least 300N. Preferably, the overall dosage form as such does not have a breakingstrength of at least 300 N, i.e. typically the breaking strength of thedosage form as such, e.g. of the tablet or capsule, is below 300 N.

When the dosage form additionally contains particle(s) B, theseparticle(s) B may also have a breaking strength of at least 300 N.However, though being less preferred, the invention also includesembodiments where optionally present particle(s) B do not have abreaking strength of at least 300 N.

Preferably, the particle(s) are tamper-resistant as such so that theyalso provide tamper-resistance after they have been separated from theremaining constituents of the dosage form. Thus, preferably theparticle(s) as such contain all ingredients that are necessary to renderthem tamper-resistant.

Preferably, when trying to tamper the dosage form in order to prepare aformulation suitable for abuse by intravenous administration, the liquidpart of the formulation that can be separated from the remainder bymeans of a syringe is as less as possible, preferably it contains notmore than 20 wt.-%, more preferably not more than 15 wt.-%, still morepreferably not more than 10 wt.-%, and most preferably not more than 5wt.-% of the originally contained pharmacologically active ingredient a.

The same may apply to optionally present pharmacologically activeingredient b. However, in a preferred embodiment pharmacologicallyactive ingredient a is more prone to abuse than optionally presentpharmacologically active ingredient b.

Preferably, this property is tested by (i) dispensing a dosage form thatis either intact or has been manually comminuted by means of two spoonsin 5 ml of purified water, (ii) heating the liquid up to its boilingpoint, (iii) boiling the liquid in a covered vessel for 5 min withoutthe addition of further purified water, (iv) drawing up the hot liquidinto a syringe (needle 21G equipped with a cigarette filter), (v)determining the amount of the pharmacologically active ingredient aand/or b contained in the liquid within the syringe.

Further, when trying to disrupt the dosage forms by means of a hammer ormortar, the particle(s) preferably tend to adhere to one another therebyforming aggregates and agglomerates, respectively, which are larger insize than the untreated particle(s).

Preferably, tamper-resistance is achieved based on the mechanicalproperties of the particle(s) so that comminution is avoided or at leastsubstantially impeded. According to the invention, the term comminutionmeans the pulverization of the particle(s) using conventional meansusually available to an abuser, for example a pestle and mortar, ahammer, a mallet or other conventional means for pulverizing under theaction of force. Thus, tamper-resistance preferably means thatpulverization of the particle(s) using conventional means is avoided orat least substantially impeded.

Preferably, the mechanical properties of the particle(s) according tothe invention, particularly their breaking strength and deformability,substantially rely on the presence and spatial distribution of a polymermatrix, preferably comprising polyalkylene oxide, although its merepresence does typically not suffice in order to achieve said properties.The advantageous mechanical properties of the particle(s) according tothe invention may not automatically be achieved by simply processingpharmacologically active ingredient a/b, the components of the polymermatrix such as polyalkylene oxide, and optionally further excipients bymeans of conventional methods for the preparation of dosage forms. Infact, usually suitable apparatuses must be selected for the preparationand critical processing parameters must be adjusted, particularlypressure/force, temperature and time. Thus, even if conventionalapparatuses are used, the process protocols usually must be adapted inorder to meet the required criteria.

In general, the particle(s) exhibiting the desired properties may beobtained only if, during preparation of the particle(s),

-   -   suitable components    -   in suitable amounts

are exposed to

-   -   a sufficient pressure    -   at a sufficient temperature    -   for a sufficient period of time.

Thus, regardless of the apparatus used, the process protocols must beadapted in order to meet the required criteria. Therefore, the breakingstrength and deformability of the particle(s) is separable from thecomposition.

The particle(s) contained in the dosage form according to the inventionpreferably have a breaking strength of at least 300 N, at least 400 N,or at least 500 N, preferably at least 600 N, more preferably at least700 N, still more preferably at least 800 N, yet more preferably atleast 1000 N, most preferably at least 1250 N and in particular at least1500 N.

In order to verify whether a particle(s) exhibits a particular breakingstrength of e.g. 300 N or 500 N it is typically not necessary to subjectsaid particle(s) to forces much higher than 300 N and 500 N,respectively. Thus, the breaking strength test can usually be terminatedonce the force corresponding to the desired breaking strength has beenslightly exceeded, e.g. at forces of e.g. 330 N and 550 N, respectively.

The “breaking strength” (resistance to crushing) of a dosage form and ofa particle(s) is known to the skilled person. In this regard it can bereferred to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, EditioCantor Verlag Aulendorf, 2002; H Liebermann et al., Dosage forms: Dosageforms, Vol. 2, Informa Healthcare; 2 edition, 1990; and Encyclopedia ofPharmaceutical Technology, Informa Healthcare; 1 edition.

For the purpose of the specification, the breaking strength ispreferably defined as the amount of force that is necessary in order tofracture the particle(s) (=breaking force). Therefore, for the purposeof the specification a particle does preferably not exhibit the desiredbreaking strength when it breaks, i.e., is fractured into at least twoindependent parts that are separated from one another.

In another preferred embodiment, however, the particle is regarded asbeing broken if the force decreases by 50% (threshold value) of thehighest force measured during the measurement (see below).

The particle(s) according to the invention are distinguished fromconventional particles that can be contained in dosage forms in that,due to their breaking strength, they cannot be pulverized by theapplication of force with conventional means, such as for example apestle and mortar, a hammer, a mallet or other usual means forpulverization, in particular devices developed for this purpose (tabletcrushers). In this regard “pulverization” means crumbling into smallparticles. Avoidance of pulverization virtually rules out oral orparenteral, in particular intravenous or nasal abuse.

Conventional particles typically have a breaking strength well below 200N.

The breaking strength of conventional round dosage forms/particle may beestimated according to the following empirical formula: BreakingStrength [in N]=10×Diameter Of The Dosage form/Particle [in mm]. Thus,according to said empirical formula, a round dosage form/particle havinga breaking strength of at least 300 N would require a diameter of atleast 30 mm. Such a particles, however, could not be swallowed, letalone a dosage form containing a plurality of such particles. The aboveempirical formula preferably does not apply to the particle(s) accordingto the invention, which are not conventional but rather special.

Further, the actual mean chewing force is 220 N (cf., e.g., P. A.Proeschel et al., J Dent Res, 2002, 81(7), 464-468). This means thatconventional particles having a breaking strength well below 200 N maybe crushed upon spontaneous chewing, whereas the particle(s) accordingto the invention may preferably not.

Still further, when applying a gravitational acceleration of 9.81 m/s²,300 N correspond to a gravitational force of more than 30 kg, i.e. theparticle(s) according to the invention can preferably withstand a weightof more than 30 kg without being pulverized.

Methods for measuring the breaking strength of a dosage form are knownto the skilled artisan. Suitable devices are commercially available.

For example, the breaking strength (resistance to crushing) can bemeasured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0, 2.09.08“Resistance to Crushing of Dosage forms”. The test is intended todetermine, under defined conditions, the resistance to crushing ofdosage forms and of the particle(s), respectively, measured by the forceneeded to disrupt them by crushing. The apparatus consists of 2 jawsfacing each other, one of which moves towards the other. The flatsurfaces of the jaws are perpendicular to the direction of movement. Thecrushing surfaces of the jaws are flat and larger than the zone ofcontact with the dosage form and a single particle, respectively. Theapparatus is calibrated using a system with a precision of 1 Newton. Thedosage form and particle, respectively, is placed between the jaws,taking into account, where applicable, the shape, the break-mark and theinscription; for each measurement the dosage form and particle,respectively, is oriented in the same way with respect to the directionof application of the force (and the direction of extension in which thebreaking strength is to be measured). The measurement is carried out on10 dosage forms and particles, respectively, taking care that allfragments have been removed before each determination. The result isexpressed as the mean, minimum and maximum values of the forcesmeasured, all expressed in Newton.

A similar description of the breaking strength (breaking force) can befound in the USP. The breaking strength can alternatively be measured inaccordance with the method described therein where it is stated that thebreaking strength is the force required to cause a dosage form andparticle, respectively, to fail (i.e., break) in a specific plane. Thedosage forms and particle, respectively, are generally placed betweentwo platens, one of which moves to apply sufficient force to the dosageform and particle, respectively, to cause fracture. For conventional,round (circular cross-section) dosage forms and particles, respectively,loading occurs across their diameter (sometimes referred to as diametralloading), and fracture occurs in the plane. The breaking force of adosage form and a particle, respectively, is commonly called hardness inthe pharmaceutical literature; however, the use of this term ismisleading. In material science, the term hardness refers to theresistance of a surface to penetration or indentation by a small probe.The term crushing strength is also frequently used to describe theresistance of dosage forms and particles, respectively, to theapplication of a compressive load. Although this term describes the truenature of the test more accurately than does hardness, it implies thatdosage forms and particles, respectively, are actually crushed duringthe test, which is often not the case.

Alternatively, the breaking strength (resistance to crushing) can bemeasured in accordance with WO 2008/107149, which can be regarded as amodification of the method described in the Eur. Ph. The apparatus usedfor the measurement is preferably a “Zwick Z 2.5” materials tester,F_(max)=2.5 kN with a maximum draw of 1150 mm, which should be set upwith one column and one spindle, a clearance behind of 100 mm and a testspeed adjustable between 0.1 and 800 mm/min together with testControlsoftware. A skilled person knows how to properly adjust the test speed,e.g. to 10 mm/min, 20 mm/min, or 40 mm/min, for example. Measurement isperformed using a pressure piston with screw-in inserts and a cylinder(diameter 10 mm), a force transducer, F_(max). 1 kN, diameter=8 mm,class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with manufacturer'stest certificate M according to DIN 55350-18 (Zwick gross forceF_(max)=1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany)with Order No BTC-FR 2.5 TH. D09 for the tester, Order No BTC-LC 0050N.P01 for the force transducer, Order No BO 70000 S06 for the centringdevice.

When using the testControl software (testXpert V10.11), the followingexemplified settings and parameters have revealed to be useful:LE-position: clamping length 150 mm. LE-speed: 500 mm/min, clampinglength after pre-travel: 195 mm, pre-travel speed: 500 mm/min, nopre-force control—pre-force: pre-force 1N, pre-force speed 10mm/min—sample data: no sample form, measuring length traverse distance10 mm, no input required prior to testing—testing/end of test; testspeed: position-controlled 10 mm/min, delay speed shift: 1, force shutdown threshold 50% F_(max), no force threshold for break-tests, no maxlength variation, upper force limit: 600N—expansion compensation: nocorrection of measuring length—actions after testing: LE to be set aftertest, no unload of sample—TRS: data memory: TRS distance interval untilbreak 1 TRS time interval 0.1 s, TRS force interval 1N—machine; traversedistance controller: upper soft end 358 mm, lower soft end 192 mm—lowertest space. Parallel arrangement of the upper plate and the ambos shouldbe ensured—these parts must not touch during or after testing. Aftertesting, a small gap (e.g. 0.1 or 0.2 mm) should still be presentbetween the two brackets in intimated contact with the tested particle,representing the remaining thickness of the deformed particle.

In a preferred embodiment, the particle is regarded as being broken ifit is fractured into at least two separate pieces of comparablemorphology. Separated matter having a morphology different from that ofthe deformed particle, e.g. dust, is not considered as pieces qualifyingfor the definition of breaking.

The particle(s) according to the invention preferably exhibit mechanicalstrength over a wide temperature range, in addition to the breakingstrength (resistance to crushing) optionally also sufficient hardness,yield strength, fatigue strength, impact resistance, impact elasticity,tensile strength, compressive strength and/or modulus of elasticity,optionally also at low temperatures (e.g. below −24° C., below −40° C.or possibly even in liquid nitrogen), for it to be virtually impossibleto pulverize by spontaneous chewing, grinding in a mortar, pounding,etc. Thus, preferably, the comparatively high breaking strength of theparticle(s) according to the invention is maintained even at low or verylow temperatures, e.g., when the dosage form is initially chilled toincrease its brittleness, for example to temperatures below −25° C.,below −40° C. or even in liquid nitrogen.

The particle(s) according to the invention are preferably characterizedby a certain degree of breaking strength. This does not mean that theparticle(s) must also exhibit a certain degree of hardness. Hardness andbreaking strength are different physical properties. Therefore, thetamper-resistance of the dosage form does not necessarily depend on thehardness of the particle(s). For instance, due to their breakingstrength, impact strength, elasticity modulus and tensile strength,respectively, the particle(s) can preferably be deformed, e.g.plastically, when exerting an external force, for example using ahammer, but cannot be pulverized, i.e., crumbled into a high number offragments. In other words, the particle(s) according to the inventionare preferably characterized by a certain degree of breaking strength,but not necessarily also by a certain degree of form stability.

Therefore, in the meaning of the specification, a particle that isdeformed when being exposed to a force in a particular direction ofextension but that does not break (plastic deformation or plastic flow)is preferably to be regarded as having the desired breaking strength insaid direction of extension.

Preferred particle(s) present in the dosage forms according to theinvention are those having a suitable tensile strength as determined bya test method currently accepted in the art. Further preferredparticle(s) are those having a Youngs Modulus as determined by a testmethod of the art. Still further preferred particle(s) are those havingan acceptable elongation at break.

Irrespective of whether the particle(s) according to the invention havean increased breaking strength or nor, the particle(s) according to theinvention preferably exhibit a certain degree of deformability. Theparticle(s) contained in the dosage form according to the inventionpreferably have a deformability such that they show an increase,preferably a substantially steady increase of the force at acorresponding decrease of the displacement in theforce-displacement-diagram when being subjected to a breaking strengthtest as described above.

This mechanical property, i.e. the deformability of the individualparticle(s), is illustrated in FIGS. 1 and 2.

FIG. 1 schematically illustrates the measurement and the correspondingforce-displacement-diagram. In particular, FIG. 1A shows the initialsituation at the beginning of the measurement. The sample particle (2)is placed between upper jaw (1 a) and lower jaw (1 b) which each are inintimate contact with the surface of the particle (2). The initialdisplacement d₀ between upper jaw (1 a) and lower jaw (1 b) correspondsto the extension of the particle orthogonal to the surfaces of upper jaw(1 a) and lower jaw (1 b). At this time, no force is exerted at all andthus, no graph is displayed in the force-displacement-diagram below.When the measurement is commenced, the upper jaw is moved in directionof lower jaw (1 b), preferably at a constant speed. FIG. 1B shows asituation where due to the movement of upper jaw (1 a) towards lower jaw(1 b) a force is exerted on particle (2). Because of its deformability,the particle (2) is flattened without being fractured. Theforce-displacement-diagram indicates that after a reduction of thedisplacement d₀ of upper jaw (1 a) and lower jaw (1 b) by distance x₁,i.e. at a displacement of d₁=d₀−x₁, a force F₁ is measured. FIG. 1Cshows a situation where due to the continuous movement of upper jaw (1a) towards lower jaw (1 b), the force that is exerted on particle (2)causes further deformation, although the particle (2) does not fracture.The force-displacement-diagram indicates that after a reduction of thedisplacement d₀ of upper jaw (1 a) and lower jaw (1 b) by distance x₂,i.e. at a displacement of d₂=d₀−x₂, a force F₂ is measured. Under thesecircumstances, the particle (2) has not been broken (fractured) and asubstantially steady increase of the force in theforce-displacement-diagram is measured.

In contrast, FIG. 2 schematically illustrates the measurement and thecorresponding force-displacement-diagram of a conventional comparativeparticle not having the degree of deformability as the particle(s)according to the invention. FIG. 2A shows the initial situation at thebeginning of the measurement. The comparative sample particle (2) isplaced between upper jaw (1 a) and lower jaw (1 b) which each are inintimate contact with the surface of the comparative particle (2). Theinitial displacement d₀ between upper jaw (1 a) and lower jaw (1 b)corresponds to the extension of the comparative particle orthogonal tothe surfaces of upper jaw (1 a) and lower jaw (1 b). At this time, noforce is exerted at all and thus, no graph is displayed in theforce-displacement-diagram below. When the measurement is commenced, theupper jaw is moved in direction of lower jaw (1 b), preferably at aconstant speed. FIG. 2B shows a situation where due to the movement ofupper jaw (1 a) towards lower jaw (1 b) a force is exerted oncomparative particle (2). Because of some deformability, the comparativeparticle (2) is slightly flattened without being fractured. Theforce-displacement-diagram indicates that after a reduction of thedisplacement d₀ of upper jaw (1 a) and lower jaw (1 b) by distance x₁,i.e. at a displacement of d₁=d₀−x₁, a force F₁ is measured. FIG. 2Cshows a situation where due to the continuous movement of upper jaw (1a) towards lower jaw (1 b), the force that is exerted on particle (2)causes sudden fracture of the comparative particle (2). Theforce-displacement-diagram indicates that after a reduction of thedisplacement d₀ of upper jaw (1 a) and lower jaw (1 b) by distance x₂,i.e. at a displacement of d₂=d₀−x₂, a force F₂ is measured that suddenlydrops when the particle fractures. Under these circumstances, theparticle (2) has been broken (fractured) and no steady increase of theforce in the force-displacement-diagram is measured. The sudden drop(decrease) of the force can easily be recognized and does not need to bequantified for the measurement. The steady increase in theforce-displacement-diagram ends at displacement d₂=d₀−x₂ when theparticle breaks.

In a preferred embodiment, the particle(s) contained in the dosage formaccording to the invention have a deformability such that they show anincrease, preferably a substantially steady increase of the force at acorresponding decrease of the displacement in theforce-displacement-diagram when being subjected to a breaking strengthtest as described above (“Zwick Z 2.5” materials tester, constantspeed), preferably at least until the displacement d of upper jaw (1 a)and lower jaw (1 b) has been reduced to a value of 90% of the originaldisplacement d₀ (i.e. d=0.9·d₀), preferably to a displacement d of 80%of the original displacement d₀, more preferably to a displacement d of70% of the original displacement d₀, still more preferably to adisplacement d of 60% of the original displacement d₀, yet morepreferably to a displacement d of 50% of the original displacement d₀,even more preferably to a displacement d of 40% of the originaldisplacement d₀, most preferably to a displacement d of 30% of theoriginal displacement d₀, and in particular to a displacement d of 20%of the original displacement d₀, or to a displacement d of 15% of theoriginal displacement d₀, to a displacement d of 10% of the originaldisplacement d₀, or to a displacement d of 5% of the originaldisplacement d₀.

In another preferred embodiment, the particle(s) contained in the dosageform according to the invention have a deformability such that they showan increase, preferably a substantially steady increase of the force ata corresponding decrease of the displacement in theforce-displacement-diagram when being subjected to a breaking strengthtest as described above (“Zwick Z 2.5” materials tester, constantspeed), preferably at least until the displacement d of upper jaw (1 a)and lower jaw (1 b) has been reduced to 0.80 mm or 0.75 mm, preferably0.70 mm or 0.65 mm, more preferably 0.60 mm or 0.55 mm, still morepreferably 0.50 mm or 0.45 mm, yet more preferably 0.40 mm or 0.35 mm,even more preferably 0.30 mm or 0.25 mm, most preferably 0.20 mm or 0.15mm and in particular 0.10 or 0.05 mm.

In still another preferred embodiment, the particle(s) contained in thedosage form according to the invention have a deformability such thatthey show an increase, preferably a substantially steady increase of theforce at a corresponding decrease of the displacement in theforce-displacement-diagram when being subjected to a breaking strengthtest as described above (“Zwick Z 2.5” materials tester, constantspeed), at least until the displacement d of upper jaw (1 a) and lowerjaw (1 b) has been reduced to 50% of the original displacement d₀ (i.e.d=d₀/2), whereas the force measured at said displacement (d=d₀/2) is atleast 25 N or at least 50 N, preferably at least 75 N or at least 100 N,still more preferably at least 150 N or at least 200 N, yet morepreferably at least 250 N or at least 300 N, even more preferably atleast 350 N or at least 400 N, most preferably at least 450 N or atleast 500 N, and in particular at least 625 N, or at least 750 N, or atleast 875 N, or at least 1000 N, or at least 1250 N, or at least 1500 N.

In another preferred embodiment, the particle(s) contained in the dosageform according to the invention have a deformability such that they showan increase, preferably a substantially steady increase of the force ata corresponding decrease of the displacement in theforce-displacement-diagram when being subjected to a breaking strengthtest as described above (“Zwick Z 2.5” materials tester, constantspeed), at least until the displacement d of upper jaw (1 a) and lowerjaw (1 b) has been reduced by at least 0.1 mm, more preferably at least0.2 mm, still more preferably at least 0.3 mm, yet more preferably atleast 0.4 mm, even more preferably at least 0.5 mm, most preferably atleast 0.6 mm, and in particular at least 0.7 mm, whereas the forcemeasured at said displacement is within the range of from 5.0 N to 250N, more preferably from 7.5 N to 225 N, still more preferably from 10 Nto 200 N, yet more preferably from 15 N to 175 N, even more preferablyfrom 20 N to 150 N, most preferably from 25 N to 125 N, and inparticular from 30 N to 100 N.

In yet another embodiment, the particle(s) contained in the dosage formaccording to the invention have a deformability such that they aredeformed without being fractured when subjected to a constant force ofe.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breakingstrength test as described above (“Zwick Z 2.5” materials tester,constant force), until the displacement d of upper jaw (1 a) and lowerjaw (1 b) is reduced so that no further deformation takes place at saidconstant force, whereas at this equilibrated state the displacement d ofupper jaw (1 a) and lower jaw (1 b) is at most 90% of the originaldisplacement d₀ (i.e. d≤0.9·d₀), preferably at most 80% of the originaldisplacement d₀ (i.e. d≤0.8·d₀), more preferably at most 70% of theoriginal displacement d₀ (i.e. d≤0.7·d₀), still more preferably at most60% of the original displacement d₀ (i.e. d≤0.6·d₀), yet more preferablyat most 50% of the original displacement d₀ (i.e. d≤0.5·d₀), even morepreferably at most 40% of the original displacement d₀ (i.e. d≤0.4·d₀),most preferably at most 30% of the original displacement d₀ (i.e.d≤0.3·d₀), and in particular at most 20% of the original displacement d₀(i.e. d≤0.2·d₀), or at most 15% of the original displacement d₀ (i.e.d≤0.15·d₀), at most 10% of the original displacement d₀ (i.e. d≤0.1·d₀),or at most 5% of the original displacement d₀ (i.e. d≤0.05·d₀).

Preferably, the particle(s) contained in the dosage form according tothe invention have a deformability such that they are deformed withoutbeing fractured when subjected to a constant force of e.g. 50 N, 100 N,200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test asdescribed above (“Zwick Z 2.5” materials tester, constant force), untilthe displacement d of upper jaw (1 a) and lower jaw (1 b) is reduced sothat no further deformation takes place at said constant force, whereasat this equilibrated state the displacement d of upper jaw (1 a) andlower jaw (1 b) is at most 0.80 mm or at most 0.75 mm, preferably atmost 0.70 mm or at most 0.65 mm, more preferably at most 0.60 mm or atmost 0.55 mm, still more preferably at most 0.50 mm or at most 0.45 mm,yet more preferably at most 0.40 mm or at most 0.35 mm, even morepreferably at most 0.30 mm or at most 0.25 mm, most preferably at most0.20 mm or at most 0.15 mm and in particular at most 0.10 or at most0.05 mm.

In another embodiment, the particle(s) contained in the dosage formaccording to the invention have a deformability such that they aredeformed without being fractured when subjected to a constant force ofe.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a breakingstrength test as described above (“Zwick Z 2.5” materials tester,constant force), until the displacement d of upper jaw (1 a) and lowerjaw (1 b) is reduced so that no further deformation takes place at saidconstant force, whereas at this equilibrated state the displacement d ofupper jaw (1 a) and lower jaw (1 b) is at least 5% of the originaldisplacement d₀ (i.e. d≥0.05·d₀), preferably at least 10% of theoriginal displacement d₀ (i.e. d≥0.1·d₀), more preferably at least 15%of the original displacement d₀ (i.e. d≥0.15·d₀), still more preferablyat least 20% of the original displacement d₀ (i.e. d≥0.2·d₀), yet morepreferably at least 30% of the original displacement d₀ (i.e. d≥0.3·d₀),even more preferably at least 40% of the original displacement d₀ (i.e.d≥0.4·d₀), most preferably at least 50% of the original displacement d₀(i.e. d≥0.5·d₀), and in particular at least 60% of the originaldisplacement d₀ (i.e. d≥0.6·d₀), or at least 70% of the originaldisplacement d₀ (i.e. d≥0.7·d₀), at least 80% of the originaldisplacement d₀ (i.e. d≥0.8·d₀), or at least 90% of the originaldisplacement d₀ (i.e. d≥0.9·d₀).

Preferably, the particle(s) contained in the dosage form according tothe invention have a deformability such that they are deformed withoutbeing fractured when subjected to a constant force of e.g. 50 N, 100 N,200 N, 300 N, 400 N, 500 N or 600 N in a breaking strength test asdescribed above (“Zwick Z 2.5” materials tester, constant force), untilthe displacement d of upper jaw (1 a) and lower jaw (1 b) is reduced sothat no further deformation takes place at said constant force, whereasat this equilibrated state the displacement d of upper jaw (1 a) andlower jaw (1 b) is at least 0.05 mm or at least 0.10 mm, preferably atleast 0.15 mm or at least 0.20 mm, more preferably at least 0.25 mm orat least 0.30 mm, still more preferably at least 0.35 mm or at least0.40 mm, yet more preferably at least 0.45 mm or at least 0.50 mm, evenmore preferably at least 0.55 mm or at least 0.60 mm, most preferably atleast 0.65 mm or at least 0.70 mm and in particular at least 0.75 or atleast 0.80 mm.

In particularly preferred embodiments, the dosage form according to theinvention comprises a multitude of particles A which

-   -   amount to a total number within the range of from 20 to 600;        and/or    -   are made from substantially the same mixture of ingredients;        and/or    -   have substantially of the same size, shape, weight and        composition; and/or    -   have cylindrical shape; and/or    -   have substantially the same breaking strength;    -   have a breaking strength of at least 300 N; and/or    -   have an average individual weight within the range of from 0.1        mg to 5 mg; and/or    -   have a total weight within the range of from 10 mg to 500 mg;        and/or    -   amount to a total content within the range of from 10 wt.-% to        80 wt.-%, based on the total weight of the dosage form; and/or    -   are tamper-resistant as such so that they also provide        tamper-resistance after they have been separated from the        remaining constituents of the dosage form; and/or    -   contain the total amount of the pharmacologically active        ingredient a that is contained in the dosage form; and/or    -   have substantially the same content of pharmacologically active        ingredient a; and/or    -   show substantially the same in vitro release profile; and/or    -   after 30 min under in vitro conditions have released at least 80        wt.-% of the pharmacologically active ingredient a that was        originally contained in the dosage form; and/or    -   are thermoformed by hot-melt extrusion.

In preferred embodiments, the dosage form according to the inventioncomprises at least a portion of the optionally present pharmacologicallyactive ingredient b outside the particle(s) A in an outer matrixmaterial, which preferably comprises granules comprising optionallypresent pharmacologically active ingredient b and excipients selectedfrom binders, fillers, disintegrants, lubricants, and the like. Theouter matrix material may also comprise the optionally presentgranule(s) B and the optionally present portion b_(P) of the optionallypresent pharmacologically active ingredient b that is present in form ofa powder outside particle(s) A and B.

In a preferred embodiment, the total amount of the optionally presentpharmacologically active ingredient b that is contained in the dosageform according to the invention is contained outside the particle(s) Ain the outer matrix material, preferably in the granules that are partof said outer matrix material.

In another preferred embodiment, a portion b_(G) of the total amount ofthe optionally present pharmacologically active ingredient b that iscontained in the dosage form according to the invention is contained inthe outer matrix material, preferably in the granules that are part ofsaid outer matrix material, whereas the remainder of the optionallypresent pharmacologically active ingredient b is contained elsewhere inthe dosage form according to the invention.

When a portion of the optionally present pharmacologically activeingredient b is present in the one or more particle(s) A, said portionis referred to as “portion b_(A)”. Said portion b_(A) is neithercontained in particle(s) B, nor is it contained in a coating ofparticle(s) A, nor is it present in form of a powder, nor is it presentin form of granules.

When a portion of the optionally present pharmacologically activeingredient b is present outside the particle(s) A in one or moreparticle(s) B, said portion is referred to as “portion b_(B)”. Saidportion b_(B) is neither contained in particle(s) A, nor is it containedin a coating of particle(s) A, nor is it present in form of a powder,nor is it present in form of granules.

When a portion of the optionally present pharmacologically activeingredient b is present outside the particle(s) A in a coating ofparticle(s) A, said portion is referred to as “portion b_(C)”. Saidportion b_(C) is neither contained in particle(s) A, nor is it containedin particle(s) A, nor is it present in form of a powder, nor is itpresent in form of granules.

When a portion of the optionally present pharmacologically activeingredient b is present outside the particle(s) A in the outer matrixmaterial, preferably in the granules that are part of said outer matrixmaterial, said portion is referred to as “portion b_(G)”. Said portionb_(G) is neither contained in particle(s) A, nor is it contained in acoating of particle(s) A, nor is it contained in particle(s) B, nor isit present in form of a powder.

When a portion of the optionally present pharmacologically activeingredient b is present outside the particle(s) A in form of a powder,said portion is referred to as “portion b_(P)”. Said portion b_(P) isneither contained in particle(s) A, nor is it contained in a coating ofparticle(s) A, nor is it contained in particle(s) B, nor is it presentin form of granules.

Preferably, when the total amount of the optionally presentpharmacologically active ingredient b is divided into portions that arepresent at different locations of the dosage form, the total amount ofthe optionally present pharmacologically active ingredient b ispreferably divided in not more than three portions, more preferably notmore than two portions.

Thus, when the total amount of the optionally present pharmacologicallyactive ingredient b is divided into two portions, portion b_(G) ispresent the outer matrix material, preferably in the granules that arepart of said outer matrix material, whereas preferably the entireremainder amount of the optionally present pharmacologically activeingredient b, which is not present in the granules that are part of saidouter matrix material, is present either as portion b_(A) in theparticle(s) A, or as portion b_(B) in particle(s) B, or as portion b_(C)in a coating of particle(s) A, or as portion b_(P) outside particle(s) Ain form of a powder.

Preferably, the relative weight ratio of portion b_(G) to portion b_(A),or the relative weight ratio of portion b_(G) to portion b_(B), or therelative weight ratio of portion b_(G) to portion b_(C), or the relativeweight ratio of portion b_(G) to portion b_(P), is within the range offrom 100:1 to 1:100, more preferably 50:1 to 1:50, still more preferably10:1 to 1:10, yet more preferably 5:1 to 1:5.

In a preferred embodiment, the weight of portion b_(G) is greater thanthe weight of portion b_(A), or the weight of portion b_(G) is greaterthan the weight of portion b_(B), or the weight of portion b_(G) isgreater than the weight of portion b_(C), or the weight of portion b_(G)is greater than the weight of portion b_(P).

In another preferred embodiment, the weight of portion b_(A) is greaterthan the weight of portion b_(G), or the weight of portion b_(B) isgreater than the weight of portion b_(G), or the weight of portion b_(C)is greater than the weight of portion b_(G), or the weight of portionb_(P) is greater than the weight of portion b_(G).

In a preferred embodiment, the dosage form according to the invention isa tablet, wherein the particle(s) A are contained in an outer matrixmaterial. The “outer matrix material” is not to be confused with the“polymer matrix” of the particle(s) A and the optionally presentparticle(s) B. In the following, this preferred embodiment is referredto as the “preferred tablet according to the invention”.

When the preferred tablet according to the invention comprisesparticle(s) B, the following preferred embodiments described forparticles(s) A may also analogously and independently apply toparticle(s) B. Thus, in the following it is generally referred to “theparticle(s)” when no specific distinction between particle(s) A and theoptionally present particle(s) B is necessary, nevertheless implying thequality and quantity of particle(s) A and particle(s) B are stillindependent of one another.

The preferred tablet according to the invention comprises subunitshaving different morphology and properties, namely particle(s) and outermatrix material, wherein the particle(s) form a discontinuous phasewithin the outer matrix material. The particle(s) typically havemechanical properties that differ from the mechanical properties of theouter matrix material. Preferably, the particle(s) have a highermechanical strength than the outer matrix material. The particle(s)within the preferred tablet according to the invention can be visualizedby conventional means such as x-ray, solid state nuclear magneticresonance spectroscopy, raster electron microscopy, terahertzspectroscopy and the like.

In the preferred tablet according to the invention, the particle(s) areincorporated in an outer matrix material. From a macroscopicperspective, the outer matrix material preferably forms a continuousphase in which the particle(s) are embedded as discontinuous phase.

Preferably, the outer matrix material is a homogenous coherent mass,preferably a homogeneous mixture of solid constituents, in which theparticle(s) are embedded thereby spatially separating the particle(s)from one another. While it is possible that the surfaces of particle(s)are in contact or at least in very close proximity with one another, theplurality of particle(s) preferably cannot be regarded as a singlecontinuous coherent mass within the preferred tablet according to theinvention.

In other words, the preferred tablet according to the inventioncomprises the particle(s) as volume element(s) of a first type in whichthe pharmacologically active ingredient a and the polymer matrix, whichpreferably comprises polyalkylene oxide, are contained, preferablyhomogeneously, and the outer matrix material as volume element of asecond type differing from the material that forms the particle(s),preferably containing neither pharmacologically active ingredient a/bnor polymer matrix, polyalkylene oxide, but optionally polyethyleneglycol which differs from polyethylene oxide in its molecular weight.

When portion b_(P) of the pharmacologically active ingredient is presentin form of a powder, said powder is a constituent of the outer matrixmaterial of the preferred tablet according to the invention. Whenportion b_(G) of the pharmacologically active ingredient is present inform of granules, said granules are a constituent of the outer matrixmaterial of the preferred tablet according to the invention.

A purpose of the outer matrix material in the preferred tablet accordingto the invention is to ensure rapid disintegration and subsequentrelease of the pharmacologically active ingredients a and b from thedisintegrated preferred tablet according to the invention, i.e. from theparticle(s) A and optionally from particle(s) B, from the coating ofparticle(s) A, from the granules and from the powder, respectively.Thus, the outer matrix material preferably does not contain anyexcipient that might have a retardant effect on disintegration and drugrelease, respectively. Thus, the outer matrix material preferably doesnot contain any polymer that is typically employed as outer matrixmaterial in prolonged release formulations.

The preferred tablet according to the invention preferably comprises theouter matrix material in an amount of more than one third of the totalweight of the preferred tablet according to the invention. Thus, thepolymer matrix which preferably comprises polyalkylene oxide and whichis contained in the particle(s) A of the preferred tablet according tothe invention is preferably not also contained in the outer matrixmaterial.

Preferably, the pharmacologically active ingredient a which is containedin the particle(s) A of the preferred tablet according to the inventionis preferably not also contained in the outer matrix material. Thus, ina preferred embodiment, the total amount of pharmacologically activeingredient a contained in the preferred tablet according to theinvention is present in the particle(s) A which form a discontinuousphase within the outer matrix material; and the outer matrix materialforming a continuous phase does not contain any pharmacologically activeingredient a.

Preferably, the optionally present pharmacologically active ingredientb, at least a portion of which is preferably present as a powder and/orin form of granules, is contained in the outer matrix material, whereascompaction of the preferred tablet according to the invention hastypically caused compaction of said powder and/or granules, typically inadmixture with the other constituents of the outer matrix material.

Preferably, the content of the outer matrix material is at least 35wt.-%, at least 37.5 wt.-% or at least 40 wt.-%; more preferably atleast 42.5 wt.-%, at least 45 wt.-%, at least 47.5 wt.-% or at least 50wt.-%; still more preferably at least 52.5 wt.-%, at least 55 wt.-%, atleast 57.5 wt.-% or at least 60 wt.-%; yet more preferably at least 62.5wt.-%, at least 65 wt.-%, at least 67.5 wt.-% or at least 60 wt.-%; mostpreferably at least 72.5 wt.-%, at least 75 wt.-%, at least 77.5 wt.-%or at least 70 wt.-%; and in particular at least 82.5 wt.-%, at least 85wt.-%, at least 87.5 wt.-% or at least 90 wt.-%; based on the totalweight of the preferred tablet according to the invention.

Preferably, the content of the outer matrix material is at most 90wt.-%, at most 87.5 wt.-%, at most 85 wt.-%, or at most 82.5 wt.-%; morepreferably at most 80 wt.-%, at most 77.5 wt.-%, at most 75 wt.-% or atmost 72.5 wt.-%; still more preferably at most 70 wt.-%, at most 67.5wt.-%, at most 65 wt.-% or at most 62.5 wt.-%; yet more preferably atmost 60 wt.-%, at most 57.5 wt.-%, at most 55 wt.-% or at most 52.5wt.-%; most preferably at most 50 wt.-%, at most 47.5 wt.-%, at most 45wt.-% or at most 42.5 wt.-%; and in particular at most 40 wt.-%, at most37.5 wt.-%, or at most 35 wt.-%; based on the total weight of thepreferred tablet according to the invention.

In a preferred embodiment, the content of the outer matrix material iswithin the range of 40±5 wt.-%, more preferably 40±2.5 wt.-%, based onthe total weight of the preferred tablet according to the invention. Inanother preferred embodiment, the content of the outer matrix materialis within the range of 45±10 wt.-%, more preferably 45±7.5 wt.-%, stillmore preferably 45±5 wt.-%, and most preferably 45±2.5 wt.-%, based onthe total weight of the preferred tablet according to the invention. Instill another preferred embodiment, the content of the outer matrixmaterial is within the range of 50±10 wt.-%, more preferably 50±7.5wt.-%, still more preferably 50±5 wt.-%, and most preferably 50±2.5wt.-%, based on the total weight of the preferred tablet according tothe invention. In yet another preferred embodiment, the content of theouter matrix material is within the range of 55±10 wt.-%, morepreferably 55±7.5 wt.-%, still more preferably 55±5 wt.-%, and mostpreferably 55±2.5 wt.-%, based on the total weight of the preferredtablet according to the invention.

Preferably, the outer matrix material is a mixture, preferably ahomogeneous mixture of at least two different constituents, morepreferably of at least three different constituents. In a preferredembodiment, all constituents of the outer matrix material arehomogeneously distributed in the continuous phase that is formed by theouter matrix material.

Preferably, the outer matrix material is a homogenous powdery orcoherent mass, preferably a homogeneous mixture of solid constituents,in which the particle(s) A are embedded. According to this embodiment,the particle(s) A are preferably spatially separated from one another.While it is possible that the surfaces of particle(s) A are in contactor at least in very close proximity with one another, the plurality ofparticle(s) A preferably cannot be regarded as a single continuouscoherent mass within the dosage form.

The dosage form according to the invention may contain additionalpharmaceutical excipients conventionally contained in dosage forms inconventional amounts, such as fillers, binders, dispersing agents,wetting agents, disintegrants, gelling agents, antioxidants,preservatives, lubricants, plasticizer, fillers, binders, and the like.

Said excipients may independently of one another be present in theparticle(s) A, the matrix material of the preferred tablet according tothe invention, the optionally present particle(s) B, the optionallypresent coating of particle(s) A, and the optionally present granules,respectively.

The skilled person will readily be able to determine appropriateexcipients as well as the quantities of each of these excipients.Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate the dosage forms according to theinvention are described in the Handbook of Pharmaceutical Excipients,American Pharmaceutical Association (1986).

Preferably, the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules independently comprise one or morefillers or binders. As many fillers can be regarded as binders and viceversa, for the purpose of the specification “filler/binder” refers toany excipient that is suitable as filler, binder or both. Thus, theparticle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules independently preferably comprise afiller/binder.

Preferred fillers (=filler/binders) are selected from the groupconsisting of silicium dioxide (e.g. Aerosil®), microcrystallinecellulose (e.g. Avicel®, Elcema®, Emocel®, ExCel®, Vitacell®); celluloseether (e.g. Natrosol®, Klucel®, Methocel®, Blanose®, Pharmacoat®,Viscontran®); mannitol; dextrines; dextrose; calciumhydrogen phosphate(e.g. Emcompress®); tricalcium phosphate, maltodextrine (e.g. Emdex®);lactose (e.g. Fast-Flow Lactose®; Ludipress®° Dosage Formtose®,Zeparox®); polyvinylpyrrolidone (PVP) (e.g. Kollidone®, Polyplasdone®,Polydone®); saccharose (e.g. Nu-Tab®, Sugar Tab®); magnesium salts (e.g.MgCO₃, MgO, MgSiO₃); starches and pretreated starches (e.g. Prejel®,Primotab® ET, Starch® 1500). Preferred binders are selected from thegroup consisting of alginates; chitosanes; and any of the fillersmentioned above (=fillers/binders).

Some fillers/binders may also serve other purposes. It is known, forexample, that silicium dioxide exhibits excellent function as a glidant.Preferably, the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules independently comprise a glidantsuch as silicium dioxide.

In a preferred embodiment, the content of the filler/binder or mixtureof fillers/binders in the particle(s), the coating, the outer matrixmaterial, the capsule filling, and/or the granules independently iswithin the range of 50±25 wt.-%, more preferably 50±20 wt.-%, still morepreferably 50±15 wt.-%, yet more preferably 50±10 wt.-%, most preferably50±7.5 wt.-%, and in particular 50±5 wt.-%, based on the total weight ofthe particle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules, respectively. In another preferredembodiment, the content of the filler/binder or mixture offillers/binders in the particle(s), the coating, the outer matrixmaterial, the capsule filling, and/or the granules independently iswithin the range of 65±25 wt.-%, more preferably 65±20 wt.-%, still morepreferably 65±15 wt.-%, yet more preferably 65±10 wt.-%, most preferably65±7.5 wt.-%, and in particular 65±5 wt.-%, based on the total weight ofthe particle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules, respectively. In still another preferredembodiment, the content of the filler/binder or mixture offillers/binders in the particle(s), the coating, the outer matrixmaterial, the capsule filling, and/or the granules independently iswithin the range of 80±19 wt.-%, more preferably 80±17.5 wt.-%, stillmore preferably 80±15 wt.-%, yet more preferably 80±10 wt.-%, mostpreferably 80±7.5 wt.-%, and in particular 80±5 wt.-%, based on thetotal weight of the particle(s), the coating, the outer matrix material,the capsule filling, and/or the granules, respectively. In anotherpreferred embodiment, the content of the filler/binder or mixture offillers/binders in the particle(s), the coating, the outer matrixmaterial, the capsule filling, and/or the granules independently iswithin the range of 90±9 wt.-%, more preferably 90±8 wt.-%, still morepreferably 90±7 wt.-%, yet more preferably 90±6 wt.-%, most preferably90±5 wt.-%, and in particular 90±4 wt.-%, based on the total weight ofthe particle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules, respectively.

In a preferred embodiment, the total content of the filler/binder ormixture of fillers/binders in the dosage form is within the range of25±24 wt.-%, more preferably 25±20 wt.-%, still more preferably 25±16wt.-%, yet more preferably 25±12 wt.-%, most preferably 25±8 wt.-%, andin particular 25±4 wt.-%, based on the total weight of dosage form. Inanother preferred embodiment, the total content of the filler/binder ormixture of fillers/binders in the dosage form is within the range of30±29 wt.-%, more preferably 30±25 wt.-%, still more preferably 30±20wt.-%, yet more preferably 30±15 wt.-%, most preferably 30±10 wt.-%, andin particular 30±5 wt.-%, based on the total weight of dosage form. Instill another preferred embodiment, the total content of thefiller/binder or mixture of fillers/binders in the dosage form is withinthe range of 35±34 wt.-%, more preferably 35±28 wt.-%, still morepreferably 35±22 wt.-%, yet more preferably 35±16 wt.-%, most preferably35±10 wt.-%, and in particular 35±4 wt.-%, based on the total weight ofdosage form. In another preferred embodiment, the total content of thefiller/binder or mixture of fillers/binders in the dosage form is withinthe range of 40±39 wt.-%, more preferably 40±32 wt.-%, still morepreferably 40±25 wt.-%, yet more preferably 40±18 wt.-%, most preferably40±11 wt.-%, and in particular 40±4 wt.-%, based on the total weight ofdosage form.

In a preferred embodiment, particularly when the dosage form is acapsule, the capsule is preferably filled with particle(s) A, which areoptionally coated comprising portion b_(C) of the optionally presentpharmacologically active ingredient b, and/or with the outer matrixmaterial and/or with portion b_(P) of the optionally presentpharmacologically active ingredient b in form of a powder, and/or withoptionally present particle(s) B, and/or with the optionally presentgranules comprising portion b_(G) of the optionally presentpharmacologically active ingredient b; and additionally with afiller/binder, preferably lactose or mannitol.

In a preferred embodiment, the total content of the filler/binder ispreferably within the range of 25±20 wt.-%, more preferably 25±15 wt.-%,still more preferably 25±10 wt.-%, and most preferably 25±5 wt.-%, basedon the total weight of the dosage form. In another preferred embodiment,the total content of the filler/binder is preferably within the range of35±30 wt.-%, more preferably 35±25 wt.-%, still more preferably 35±20wt.-%, yet more preferably 35±15 wt.-%, even more preferably 35±10wt.-%, and most preferably 35±5 wt.-%, based on the total weight of thedosage form. In still another preferred embodiment, the total content ofthe filler/binder is preferably within the range of 45±40 wt.-%, morepreferably 45±35 wt.-%, still more preferably 45±30 wt.-%, yet morepreferably 45±25 wt.-%, even more preferably 45±20 wt.-%, and mostpreferably 45±15 wt.-%, and in particular 45±10 wt.-%, based on thetotal weight of the dosage form. In yet another preferred embodiment,the total content of the filler/binder is preferably within the range of55±40 wt.-%, more preferably 55±35 wt.-%, still more preferably 55±30wt.-%, yet more preferably 55±25 wt.-%, even more preferably 55±20wt.-%, and most preferably 55±15 wt.-%, and in particular 55±10 wt.-%,based on the total weight of the dosage form. In another preferredembodiment, the total content of the filler/binder is preferably withinthe range of 65±30 wt.-%, more preferably 65±25 wt.-%, still morepreferably 65±20 wt.-%, yet more preferably 65±15 wt.-%, even morepreferably 65±10 wt.-%, and most preferably 65±5 wt.-%, based on thetotal weight of the dosage form.

It has been surprisingly found that the filler/binder in the capsulefilling can accelerate in vitro release of the pharmacologically activeingredient a and/or of the optionally present pharmacologically activeingredient b from the dosage form according to the invention.

Preferably, the filler/binder is contained in the optionally presentparticle(s) B but not in the particle(s) A of the dosage form accordingto the invention.

Preferably, the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules independently comprise adisintegrant, wherein the content of the disintegrant is more than 5.0wt.-%, based on the total weight of the dosage form and/or based on thetotal weight of the particle(s), the coating, the outer matrix material,the capsule filling, and/or the granules, respectively.

In a preferred embodiment, particularly when the dosage form is acapsule, the dosage form contains the entire amount of disintegrantwithin the particle(s), i.e. outside the particle(s) there is preferablyno disintegrant. Furthermore, the disintegrant is preferablyhomogeneously distributed in the particle(s). Preferably, when theparticle(s) are coated, the coating does not contain disintegrant.

In another preferred embodiment, particularly when the dosage form is atablet, the dosage form contains the disintegrant within the particle(s)as well as outside the particle(s). In a preferred embodiment, thenature of disintegrant within the particle(s) is identical with thenature of disintegrant outside the particle(s). However, differentdisintegrants inside the particle(s) and outside the particle(s) arealso possible in accordance with the invention. Furthermore, thedisintegrant is preferably homogeneously distributed in the particle(s).Preferably, when the particle(s) are coated, the coating does notcontain disintegrant.

In still another preferred embodiment, particularly when the dosage formis the preferred tablet according to the invention, the dosage formcontains the disintegrant outside the particle(s), and optionally alsowithin the particle.

Suitable disintegrants are known to the skilled person and arepreferably selected from the group consisting of starches, starchderivatives, cellulose derivatives and gas releasing substances.Croscarmellose ist particularly preferred as disintegrant.

Preferred starches include but are not limited to “standard starch”(e.g. native maize starch) and pregelatinized starch (e.g. starch 1500).

Preferred starch derivatives include but are not limited to sodiumstarch glycolate (e.g. Vivastar®).

Preferred cellulose derivatives include but are not limited tocroscarmellose sodium (=crosslinked sodium carboxymethylcellulose; e.g.Vivasol®).

Preferred gas releasing substances include but are not limited to sodiumbicarbonate.

Preferred disintegrants include but are not limited to crosslinkedsodium carboxy-methylcellulose (Na-CMC) (e.g. Crosscarmellose, Vivasol®,Ac-Di-Sol®); crosslinked casein (e.g. Esma-Spreng®); polysaccharidemixtures obtained from soybeans (e.g. Emcosoy); maize starch orpretreated maize starch (e.g. Amijel®); sodium alginate;polyvinylpyrrolidone (PVP) (e.g. Kollidone®, Polyplasdone®, Polydone®);crosslinked polyvinylpyrrolidone (PVP CI) (e.g. Polyplasdone® XL);starch and pretreated starch such as sodium carboxymethyl starch(=sodium starch glycolate, e.g. Explotab®, Prejel®, Primotab® ET,Starch® 1500, Ulmatryl®), and the mixtures thereof. Crosslinked polymersare particularly preferred disintegrants, especially crosslinked sodiumcarboxymethylcellulose (Na-CMC) or crosslinked polyvinylpyrrolidone (PVPCI).

Preferably, the content of the disintegrant is at least 6.0 wt.-%, atleast 7.0 wt.-%, at least 8.0 wt.-%, at least 9.0 wt.-%, or at least 10wt.-%, more preferably at least 12 wt.-%, still more preferably at least14 wt.-%, yet more preferably at least 15 wt.-%, even more preferably atleast 16 wt.-%, most preferably at least 18 wt.-%, and in particular atleast 19 wt.-%, based on the total weight of the dosage form and/orbased on the total weight of the particle(s), the coating, the outermatrix material, the capsule filling, and/or the granules, respectively.

In a preferred embodiment, the content of the disintegrant is within therange of 15±9.0 wt.-%, more preferably 15±8.5 wt.-%, still morepreferably 15±8.0 wt.-%, yet more preferably 15±7.5 wt.-%, mostpreferably 15±7.0 wt.-%, and in particular 15±6.5 wt.-%, based on thetotal weight of the dosage form and/or based on the total weight of theparticle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules, respectively. In still another preferredembodiment, the content of the disintegrant is within the range of15±6.0 wt.-%, more preferably 15±5.5 wt.-%, still more preferably 15±5.0wt.-%, yet more preferably 15±4.5 wt.-%, most preferably 15±4.0 wt.-%,and in particular 15±3.5 wt.-%, based on the total weight of the dosageform and/or based on the total weight of the particle(s), the coating,the outer matrix material, the capsule filling, and/or the granules,respectively. In another preferred embodiment, the content of thedisintegrant is within the range of 15±3.0 wt.-%, more preferably 15±2.5wt.-%, still more preferably 15±2.0 wt.-%, yet more preferably 15±1.5wt.-%, most preferably 15±1.0 wt.-%, and in particular 15±0.5 wt.-%,based on the total weight of the dosage form and/or based on the totalweight of the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules, respectively.

In another preferred embodiment, the content of the disintegrant iswithin the range of 20±15 wt.-% or 20±14 wt.-%, more preferably 20±13wt.-%, still more preferably 20±12 wt.-%, yet more preferably 20±11wt.-%, most preferably 20±10 wt.-%, and in particular 20±9.5 wt.-%,based on the total weight of the dosage form and/or based on the totalweight of the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules, respectively. In another preferredembodiment, the content of the disintegrant is within the range of20±9.0 wt.-%, more preferably 20±8.5 wt.-%, still more preferably 20±8.0wt.-%, yet more preferably 20±7.5 wt.-%, most preferably 20±7.0 wt.-%,and in particular 20±6.5 wt.-%, based on the total weight of the dosageform and/or based on the total weight of the particle(s), the coating,the outer matrix material, the capsule filling, and/or the granules,respectively. In still another preferred embodiment, the content of thedisintegrant is within the range of 20±6.0 wt.-%, more preferably 20±5.5wt.-%, still more preferably 20±5.0 wt.-%, yet more preferably 20±4.5wt.-%, most preferably 20±4.0 wt.-%, and in particular 20±3.5 wt.-%,based on the total weight of the dosage form and/or based on the totalweight of the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules, respectively. In another preferredembodiment, the content of the disintegrant is within the range of20±3.0 wt.-%, more preferably 20±2.5 wt.-%, still more preferably 20±2.0wt.-%, yet more preferably 20±1.5 wt.-%, most preferably 20±1.0 wt.-%,and in particular 20±0.5 wt.-%, based on the total weight of the dosageform and/or based on the total weight of the particle(s), the coating,the outer matrix material, the capsule filling, and/or the granules,respectively.

In still another preferred embodiment, the content of the disintegrantis within the range of 25±9.0 wt.-%, more preferably 25±8.5 wt.-%, stillmore preferably 25±8.0 wt.-%, yet more preferably 25±7.5 wt.-%, mostpreferably 25±7.0 wt.-%, and in particular 25±6.5 wt.-%, based on thetotal weight of the dosage form and/or based on the total weight of theparticle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules, respectively. In still another preferredembodiment, the content of the disintegrant is within the range of25±6.0 wt.-%, more preferably 25±5.5 wt.-%, still more preferably 25±5.0wt.-%, yet more preferably 25±4.5 wt.-%, most preferably 25±4.0 wt.-%,and in particular 25±3.5 wt.-%, based on the total weight of the dosageform and/or based on the total weight of the particle(s), the coating,the outer matrix material, the capsule filling, and/or the granules,respectively. In another preferred embodiment, the content of thedisintegrant is within the range of 25±3.0 wt.-%, more preferably 25±2.5wt.-%, still more preferably 25±2.0 wt.-%, yet more preferably 25±1.5wt.-%, most preferably 25±1.0 wt.-%, and in particular 25±0.5 wt.-%,based on the total weight of the dosage form and/or based on the totalweight of the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules respectively.

When the dosage form according to the invention contains more than asingle disintegrant, e.g. a mixture of two different disintegrants, theabove percentages preferably refer to the total content ofdisintegrants.

Preferably, the relative weight ratio of the polyalkylene oxide to thedisintegrant is within the range of 8:1 to 1:5, more preferably 7:1 to1:4, still more preferably 6:1 to 1:3, yet more preferably 5:1 to 1:2,most preferably 4:1 to 1:1, and in particular 3:1 to 2:1.

Preferably, the relative weight ratio of the pharmacologically activeingredient a to the disintegrant is within the range of 4:1 to 1:10,more preferably 3:1 to 1:9, still more preferably 2:1 to 1:8, yet morepreferably 1:1 to 1:7, most preferably 1:2 to 1:6, and in particular 1:3to 1:5.

The dosage form may contain a single disintegrant or a mixture ofdifferent disintegrants. Preferably, the dosage form contains a singledisintegrant.

Preferably, the dosage form according to the invention and/or theparticle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules independently further comprise anantioxidant. Suitable antioxidants include ascorbic acid, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), salts of ascorbicacid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and thederivatives thereof, coniferyl benzoate, nordihydroguajaretic acid,gallus acid esters, sodium bisulfate, particularly preferablybutylhydroxytoluene or butylhydroxyanisole and α-tocopherol. Theantioxidant is preferably present in quantities of 0.01 wt.-% to 10wt.-%, more preferably of 0.03 wt.-% to 5 wt.-%, most preferably of 0.05wt.-% to 2.5 wt.-%, based on the total weight of the dosage form and/orbased on the total weight of the particle(s), the coating, the outermatrix material, the capsule filling, and/or the granules, respectively.

In a preferred embodiment, the dosage form according to the inventionand/or the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules independently further comprise anacid, preferably citric acid. The amount of acid is preferably in therange of 0.01 wt.-% to 20 wt.-%, more preferably in the range of 0.02wt.-% to 10 wt.-%, and still more preferably in the range of 0.05 wt.-%to 5 wt.-%, and most preferably in the range of 0.1 wt.-% to 1.0 wt.-%,based on the total weight of the dosage form and/or based on the totalweight of the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules, respectively.

In a preferred embodiment, the dosage form according to the inventionand/or the particle(s), the coating, the outer matrix material, thecapsule filling, and/or the granules independently further compriseanother polymer which is preferably selected from cellulose esters andcellulose ethers, in particular hydroxypropyl methylcellulose (HPMC).

The amount of the further polymer, preferably hydroxypropylmethylcellulose, preferably ranges from 0.1 wt.-% to 30 wt.-%, morepreferably in the range of 1.0 wt.-% to 20 wt.-%, most preferably in therange of 2.0 wt.-% to 15 wt.-%, and in particular in the range of 3.5wt.-% to 10.5 wt.-%, based on the total weight of the dosage form and/orbased on the total weight of the particle(s), the coating, the outermatrix material, the capsule filling, and/or the granules, respectively.

When the polymer matrix of the particle(s) comprises polyalkylene oxide,in a preferred embodiment, the relative weight ratio of the polyalkyleneoxide to the further polymer is within the range of 4.5±2:1, morepreferably 4.5±1.5:1, still more preferably 4.5±1:1, yet more preferably4.5±0.5:1, most preferably 4.5±0.2:1, and in particular 4.5±0.1:1. Inanother preferred embodiment, the relative weight ratio of thepolyalkylene oxide to the further polymer is within the range of 8±7:1,more preferably 8±6:1, still more preferably 8±5:1, yet more preferably8±4:1, most preferably 8±3:1, and in particular 8±2:1. In still anotherpreferred embodiment, the relative weight ratio of the polyalkyleneoxide to the further polymer is within the range of 11±8:1, morepreferably 11±7:1, still more preferably 11±6:1, yet more preferably11±5:1, most preferably 11±4:1, and in particular 11±3:1.

In another preferred embodiment, the dosage form and/or the particle(s)according to the invention do not contain any further polymer besidesthe polyalkylene oxide and optionally, polyethylene glycol.

In a preferred embodiment, the dosage form according to the inventioncontains at least one lubricant. Preferably, the lubricant is containedin the dosage form outside the particle(s), i.e. the particle(s) as suchpreferably do not contain lubricant. The lubricant can be independentlycontained in the coating, the outer matrix material, and/or thegranules.

Especially preferred lubricants are selected from

-   -   magnesium stearate and stearic acid;    -   glycerides of fatty acids, including monoglycerides,        diglycerides, triglycerides, and mixtures thereof; preferably of        C₆ to C₂₂ fatty acids; especially preferred are partial        glycerides of the C₁₆ to C₂₂ fatty acids such as glycerol        behenat, glycerol palmitostearate and glycerol monostearate;    -   polyoxyethylene glycerol fatty acid esters, such as mixtures of        mono-, di- and triesters of glycerol and di- and monoesters of        macrogols having molecular weights within the range of from 200        to 4000 g/mol, e.g., macrogolglycerolcaprylocaprate,        macrogolglycerollaurate, macrogolglycerolococoate,        macrogolglycerollinoleate, macrogol-20-glycerolmonostearate,        macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate;        macrogolglycerolstearate, macrogolglycerolhydroxystearate, and        macrogolglycerolrizinoleate;    -   polyglycolyzed glycerides, such as the one known and        commercially available under the trade name “Labrasol”;    -   fatty alcohols that may be linear or branched, such as        cetylalcohol, stearylalcohol, cetylstearyl alcohol,        2-octyldodecane-1-ol and 2-hexyldecane-1-ol;    -   polyethylene glycols having a molecular weight between 10.000        and 60.000 g/mol; and    -   natural semi-synthetic or synthetic waxes, preferably waxes with        a softening point of at least 50° C., more preferably 60° C.,        and in particular carnauba wax and bees wax.

Preferably, the amount of the lubricant ranges from 0.01 wt.-% to 10wt.-%, more preferably in the range of 0.05 wt.-% to 7.5 wt.-%, mostpreferably in the range of 0.1 wt.-% to 5 wt.-%, and in particular inthe range of 0.1 wt.-% to 1 wt.-%, based on the total weight of thedosage form and/or based on the total weight of the particle(s), thecoating, the outer matrix material, the capsule filling, and/or thegranules, respectively.

In another preferred embodiment, the dosage form contains no lubricant.

Preferably, the dosage form according to the invention and/or theparticle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules independently further comprise aplasticizer. The plasticizer improves the processability of the polymermatrix that preferably comprises polyalkylene oxide. A preferredplasticizer is polyalkylene glycol, like polyethylene glycol, triacetin,fatty acids, fatty acid esters, waxes and/or microcrystalline waxes.Particularly preferred plasticizers are polyethylene glycols, such asPEG 6000 (Macrogol 6000).

Preferably, the content of the plasticizer is within the range of from0.5 to 30 wt.-%, more preferably 1.0 to 25 wt.-%, still more preferably2.5 wt.-% to 22.5 wt.-%, yet more preferably 5.0 wt.-% to 20 wt.-%, mostpreferably 6 to 20 wt.-% and in particular 7 wt.-% to 17.5 wt.-%, basedon the total weight of the dosage form and/or based on the total weightof the particle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules, respectively.

In a preferred embodiment, the plasticizer is a polyalkylene glycolhaving a content within the range of 7±6 wt.-%, more preferably 7±5wt.-%, still more preferably 7±4 wt.-%, yet more preferably 7±3 wt.-%,most preferably 7±2 wt.-%, and in particular 7±1 wt.-%, based based onthe total weight of the dosage form and/or based on the total weight ofthe particle(s), the coating, the outer matrix material, the capsulefilling, and/or the granules, respectively. In another preferredembodiment, the plasticizer is a polyalkylene glycol having a contentwithin the range of 10±8 wt.-%, more preferably 10±6 wt.-%, still morepreferably 10±5 wt.-%, yet more preferably 10±4 wt.-%, most preferably10±3 wt.-%, and in particular 10±2 wt.-%, based on the total weight ofthe dosage form and/or based on the total weight of the particle(s), thecoating, the outer matrix material, the capsule filling, and/or thegranules, respectively.

In a preferred embodiment, the relative weight ratio of the polyalkyleneoxide to the polyalkylene glycol is within the range of 5.4±2:1, morepreferably 5.4±1.5:1, still more preferably 5.4±1:1, yet more preferably5.4±0.5:1, most preferably 5.4±0.2:1, and in particular 5.4±0.1:1. Thisratio satisfies the requirements of relative high polyalkylene oxidecontent and good extrudability.

Plasticizers can sometimes act as a lubricant, and lubricants cansometimes act as a plasticizer.

In preferred compositions of the particle(s) A that are preferablyhot-melt extruded and that are contained in the dosage form according tothe invention, the polymer matrix comprises a polyalkylene oxide,preferably a polyethylene oxide with a weight average molecular weightwithin the range of from 0.5 to 15 million g/mol.

The particle(s) A comprise pharmacologically active ingredient a.Particularly preferred embodiments C¹ to C¹² are summarized in thetables here below:

perparticle A [wt.-%] C¹ C² C³ C⁴ pharmacologically active ingredient a5.50 ± 5.00 5.50 ± 4.00 5.50 ± 3.00 5.50 ± 2.00 polyalkylene oxide 60.00± 35.00 60.00 ± 30.00 60.00 ± 25.00 60.00 ± 15.00 optionally acid, e.g.citric acid 0.80 ± 0.75 0.80 ± 0.65 0.80 ± 0.50 0.80 ± 0.35 optionallyplasticizer, e.g. polyethylene glycol 14.00 ± 13.50 14.00 ± 10.00 14.00± 7.50  14.00 ± 5.00  optionally antioxidant, e.g. α-tocopherol 0.20 ±0.18 0.20 ± 0.14 0.20 ± 0.10 0.20 ± 0.06 perparticle A [wt.-%] C⁵ C⁶ C⁷C⁸ pharmacologically active ingredient a 15.00 ± 25.00 15.00 ± 20.0015.00 ± 15.00 15.00 ± 10.00 polyalkylene oxide 60.00 ± 35.00 60.00 ±30.00 60.00 ± 25.00 60.00 ± 15.00 optionally acid, e.g. citric acid 0.80± 0.75 0.80 ± 0.65 0.80 ± 0.50 0.80 ± 0.35 optionally plasticizer, e.g.polyethylene glycol 11.00 ± 8.00  11.00 ± 6.00  11.00 ± 5.00  11.00 ±4.00  optionally antioxidant, e.g. α-tocopherol 0.20 ± 0.18 0.20 ± 0.140.20 ± 0.10 0.20 ± 0.06 perparticle A [wt.-%] C⁹ C¹⁰ C¹¹ C¹²pharmacologically active ingredient a 30.00 ± 25.00 30.00 ± 20.00 30.00± 15.00 30.00 ± 10.00 polyalkylene oxide 60.00 ± 35.00 60.00 ± 30.0060.00 ± 25.00 60.00 ± 15.00 optionally acid, e.g. citric acid 0.80 ±0.75 0.80 ± 0.65 0.80 ± 0.50 0.80 ± 0.35 optionally plasticizer, e.g.polyethylene glycol 9.00 ± 8.00 9.00 ± 6.00 9.00 ± 5.00 9.00 ± 4.00optionally antioxidant, e.g. α-tocopherol 0.20 ± 0.18 0.20 ± 0.14 0.20 ±0.10 0.20 ± 0.06 (all percentages relative to the total weight of theparticle(s) A).

In a preferred embodiment of the dosage form according to the invention,the particle(s) A and/or the optionally present particle(s) B are hotmelt-extruded. Thus, the particle(s) according to the invention arepreferably prepared by melt-extrusion, although also other methods ofthermoforming may be used in order to manufacture the particle(s)according to the invention such as press-molding at elevated temperatureor heating of particle(s) that were manufactured by conventionalcompression in a first step and then heated above the softeningtemperature of the polyalkylene oxide in the particle(s) in a secondstep to form hard dosage forms. In this regards, thermoforming means theforming, or molding of a mass after the application of heat. In apreferred embodiment, the particle(s) are thermoformed by hot-meltextrusion.

In a preferred embodiment, the particle(s) are prepared by hotmelt-extrusion, preferably by means of a twin-screw-extruder. Meltextrusion preferably provides a melt-extruded strand that is preferablycut into monoliths, which are then optionally compressed and formed intoparticle(s). Preferably, compression is achieved by means of a die and apunch, preferably from a monolithic mass obtained by melt extrusion. Ifobtained via melt extrusion, the compressing step is preferably carriedout with a monolithic mass exhibiting ambient temperature, that is, atemperature in the range from 20 to 25° C. The strands obtained by wayof extrusion can either be subjected to the compression step as such orcan be cut prior to the compression step. This cutting can be performedby usual techniques, for example using rotating knives or compressedair, at elevated temperature, e.g. when the extruded stand is still warmdue to hot-melt extrusion, or at ambient temperature, i.e. after theextruded strand has been allowed to cool down. When the extruded strandis still warm, singulation of the extruded strand into extrudedparticle(s) is preferably performed by cutting the extruded strandimmediately after it has exited the extrusion die. It is possible tosubject the extruded strands to the compression step or to the cuttingstep when still warm, that is more or less immediately after theextrusion step. The extrusion is preferably carried out by means of atwin-screw extruder.

The particle(s) of the dosage form according to the invention may beproduced by different processes, the particularly preferred of which areexplained in greater detail below. Several suitable processes havealready been described in the prior art. In this regard it can bereferred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, WO2006/082097, and WO 2006/082099.

In general, the process for the production of the particle(s) accordingto the invention preferably comprises the following steps:

-   (a) mixing all ingredients;-   (b) optionally pre-forming the mixture obtained from step (a),    preferably by applying heat and/or force to the mixture obtained    from step (a), the quantity of heat supplied preferably not being    sufficient to heat the polyalkylene oxide up to its softening point;-   (c) hardening the mixture by applying heat and force, it being    possible to supply the heat during and/or before and/or after the    application of force and the quantity of heat supplied being    sufficient to heat the polyalkylene oxide at least up to its    softening point; and thereafter allowing the material to cool and    removing the force-   (d) optionally singulating the hardened mixture; and-   (e) optionally providing a film coating.

In a preferred embodiment, the mixture is compressed and subsequentlyheated. In another preferred embodiment, the mixture is heated andsubsequently compressed. In still another preferred embodiment, themixture is heated and compressed simultaneously. A skilled personrecognizes that combinations of these embodiments according to theinvention are also possible.

Heat may be supplied directly, e.g. by contact or by means of hot gassuch as hot air, or with the assistance of ultrasound; or is indirectlysupplied by friction and/or shear. Force may be applied and/or theparticle(s) may be shaped for example by direct tabletting or with theassistance of a suitable extruder, particularly by means of a screwextruder equipped with one or two screws (single-screw-extruder andtwin-screw-extruder, respectively) or by means of a planetary gearextruder.

The final shape of the particle(s) may either be provided during thehardening of the mixture by applying heat and force (step (c)) or in asubsequent step (step (e)). In both cases, the mixture of all componentsis preferably in the plastified state, i.e. preferably, shaping isperformed at a temperature at least above the softening point of thepolyalkylene oxide. However, extrusion at lower temperatures, e.g.ambient temperature, is also possible and may be preferred.

A particularly preferred process for the manufacture of the particle(s)according to the invention involves hot-melt extrusion. In this process,the particle(s) according to the invention are produced by thermoformingwith the assistance of an extruder, preferably without there being anyobservable consequent discoloration of the extrudate.

This process is characterized in that

-   a) all components are mixed,-   b) the resultant mixture is heated in the extruder at least up to    the softening point of the polyalkylene oxide and extruded through    the outlet orifice of the extruder by application of force,-   c) the still plastic extrudate is singulated and formed into the    particle(s) or-   d) the cooled and optionally reheated singulated extrudate is formed    into the particle(s).

Mixing of the components according to process step a) may also proceedin the extruder.

The components may also be mixed in a mixer known to the person skilledin the art. The mixer may, for example, be a roll mixer, shaking mixer,shear mixer or compulsory mixer.

The, preferably molten, mixture which has been heated in the extruder atleast up to the softening point of polyalkylene oxide is extruded fromthe extruder through a die with at least one bore, preferably amultitude of bores.

The process according to the invention requires the use of suitableextruders, preferably screw extruders. Screw extruders which areequipped with two screws (twin-screw-extruders) are particularlypreferred.

Preferably, extrusion is performed in the absence of water, i.e., nowater is added. However, traces of water (e.g., caused by atmospherichumidity) may be present.

The extruder preferably comprises at least two temperature zones, withheating of the mixture at least up to the softening point of thepolyalkylene oxide proceeding in the first zone, which is downstreamfrom a feed zone and optionally mixing zone. The throughput of themixture is preferably from 1.0 kg to 15 kg/hour. In a preferredembodiment, the throughput is from 0.5 kg/hour to 3.5 kg/hour. Inanother preferred embodiment, the throughput is from 4 to 15 kg/hour.

In a preferred embodiment, the die head pressure is within the range offrom 25 to 200 bar. The die head pressure can be adjusted inter alia bydie geometry, temperature profile, extrusion speed, number of bores inthe dies, screw configuration, first feeding steps in the extruder, andthe like.

The die geometry or the geometry of the bores is freely selectable. Thedie or the bores may accordingly exhibit a round, oblong or ovalcross-section, wherein the round cross-section preferably has a diameterof 0.1 mm to 2 mm, preferably of 0.5 mm to 0.9 mm. Preferably, the dieor the bores have a round cross-section. The casing of the extruder usedaccording to the invention may be heated or cooled. The correspondingtemperature control, i.e. heating or cooling, is so arranged that themixture to be extruded exhibits at least an average temperature (producttemperature) corresponding to the softening temperature of thepolyalkylene oxide and does not rise above a temperature at which thepharmacologically active ingredient a to be processed may be damaged.Preferably, the temperature of the mixture to be extruded is adjusted tobelow 180° C., preferably below 150° C., but at least to the softeningtemperature of polyalkylene oxide. Typical extrusion temperatures are120° C. and 150° C.

In a preferred embodiment, the extruder torque is within the range offrom 30 to 95%. Extruder torque can be adjusted inter alia by diegeometry, temperature profile, extrusion speed, number of bores in thedies, screw configuration, first feeding steps in the extruder, and thelike.

After extrusion of the molten mixture and optional cooling of theextruded strand or extruded strands, the extrudates are preferablysingulated. This singulation may preferably be performed by cutting upthe extrudates by means of revolving or rotating knives, wires, bladesor with the assistance of laser cutters.

Preferably, intermediate or final storage of the optionally singulatedextrudate or the final shape of the particle(s) according to theinvention is performed under oxygen-free atmosphere which may beachieved, e.g., by means of oxygen-scavengers.

The singulated extrudate may be press-formed into particle(s) in orderto impart the final shape to the particle(s).

The application of force in the extruder onto the at least plasticizedmixture is adjusted by controlling the rotational speed of the conveyingdevice in the extruder and the geometry thereof and by dimensioning theoutlet orifice in such a manner that the pressure necessary forextruding the plasticized mixture is built up in the extruder,preferably immediately prior to extrusion. The extrusion parameterswhich, for each particular composition, are necessary to give rise to adosage form with desired mechanical properties, may be established bysimple preliminary testing.

For example but not limiting, extrusion may be performed by means of atwin-screw-extruder type ZSE 18 or ZSE27 (Leistritz, Nurnberg, Germany),screw diameters of 18 or 27 mm. Screws having eccentric or blunt endsmay be used. A heatable die with a round bore or with a multitude ofbores each having a diameter of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9or 1.0 mm may be used. For a twin-screw-extruder type ZSE 18, theextrusion parameters may be adjusted e.g. to the following values:rotational speed of the screws: 120 Upm; delivery rate 2 kg/h for a ZSE18 or 5 kg/h, 10 kg/h, or even 20 kg/h and more for a ZSE27; producttemperature: in front of die 125° C. and behind die 135° C.; and jackettemperature: 110° C. The throughput can generally be increased byincreasing the number of dies at the extruder outlet.

Preferably, extrusion is performed by means of twin-screw-extruders orplanetary-gear-extruders, twin-screw extruders (co-rotating orcontra-rotating) being particularly preferred.

The particle(s) according to the invention are preferably produced bythermoforming with the assistance of an extruder without any observableconsequent discoloration of the extrudates. The particle(s) may beproduced e.g. by means of a Micro Pelletizer (Leistritz, Nurnberg,Germany).

The process for the preparation of the particle(s) according to theinvention is preferably performed continuously. Preferably, the processinvolves the extrusion of a homogeneous mixture of all components. It isparticularly advantageous if the thus obtained intermediate, e.g. thestrand obtained by extrusion, exhibits uniform properties. Particularlydesirable are uniform density, uniform distribution of the activecompound, uniform mechanical properties, uniform porosity, uniformappearance of the surface, etc. Only under these circumstances theuniformity of the pharmacological properties, such as the stability ofthe release profile, may be ensured and the amount of rejects can bekept low.

Preferably, the particle(s) according to the invention can be regardedas “extruded pellets”. The term “extruded pellets” has structuralimplications which are understood by persons skilled in the art. Aperson skilled in the art knows that pelletized dosage forms can beprepared by a number of techniques, including:

-   -   drug layering on nonpareil sugar or microcrystalline cellulose        beads,    -   spray drying,    -   spray congealing,    -   rotogranulation,    -   hot-melt extrusion,    -   spheronization of low melting materials, or    -   extrusion-spheronization of a wet mass.

Accordingly, “extruded pellets” can be obtained either by hot-meltextrusion or by extrusion-spheronization.

“Extruded pellets” can be distinguished from other types of pellets, asextruded pellets typically have a different shape. The shape of theextruded pellets is typically more cut-rod-like than perfectly globatedround.

“Extruded pellets” can be distinguished from other types of pelletsbecause they are structurally different. For example, drug layering onnonpareils yields multilayered pellets having a core, whereas extrusiontypically yields a monolithic mass comprising a homogeneous mixture ofall ingredients. Similarly, spray drying and spray congealing typicallyyield spheres, whereas extrusion typically yields cylindrical extrudateswhich can be subsequently spheronized.

The structural differences between “extruded pellets” and “agglomeratedpellets” are significant because they may affect the release of activesubstances from the pellets and consequently result in differentpharmacological profiles. Therefore, a person skilled in thepharmaceutical formulation art would not consider “extruded pellets” tobe equivalent to “agglomerated pellets”.

The dosage forms according to the invention may be prepared by anyconventional method. Suitable methods and apparatuses are known to theskilled person.

When the dosage form is a capsule, all components may be filledseparately or as admixture into the capsules. Said components mayinclude but are not limited to particle(s) A, which may optionally beprovided with a coating comprising optionally present pharmacologicallyactive ingredient b or portion b_(C) thereof, the optionally presentparticle(s) B, the optionally present powder of optionally presentpharmacologically active ingredient b, and the optionally presentgranules of optionally present pharmacologically active ingredient b,respectively.

When the dosage form is a tablet, the tablet is preferably prepared bycompression. Thus, particle(s) are preferably mixed, e.g. blended and/orgranulated (e.g. wet granulated), e.g. with matrix material of thepreferred table according to the invention, the optionally presentpowder of optionally present pharmacologically active ingredient b andthe optionally present granules of optionally present pharmacologicallyactive ingredient b, respectively, and the resulting mix (e.g. blend orgranulate) is then compressed, preferably in moulds, to form dosageforms. It is also envisaged that the particle(s) may be incorporatedinto a matrix using other processes, such as by melt granulation (e.g.using fatty alcohols and/or water-soluble waxes and/or water-insolublewaxes) or high shear granulation, followed by compression.

When the dosage forms according to the invention are manufactured bymeans of an eccentric press, the compression force is preferably withinthe range of from 5 to 30 kN, preferably from 15 to 25 kN. When thedosage forms according to the invention are manufactured by means of arotating press, the compression force is preferably within the range offrom 5 to 40 kN, in certain embodiments >25 kN, in other embodiments 13kN.

The pharmaceutical dosage form according to the invention preferablycomprises no wax ingredients. Wax ingredients include fatty acid esters,glycerol fatty acid esters, fatty glyceride derivatives, waxes, andfatty alcohols such as, for example, glycerol behenate, glycerolpalmitostearate, glycerol monostearate, stearoyl macroglycerides. Otherwaxes more generally include insect and animal waxes, vegetable waxes,mineral waxes, petroleum waxes, and synthetic waxes; particularlyexamples include beeswax, carnauba wax, condelilla wax, montan wax,ouricury wax, rice-bran wax, jojoba wax, microcrystalline wax, cetylester wax, cetyl alcohol, anionic emulsifying wax, nonionic emulsifyingwax and paraffin wax.

The pharmaceutical dosage form according to the invention comprisesparticle(s) A which preferably neither comprise an active pharmaceuticallayer comprising a pharmacologically active ingredient nor a layercomprising a pH-sensitive film comprising a pH-sensitive polymer that isinsoluble in water at a pH greater than 5 and is soluble in water at apH below 5.

The particle(s) A and dosage forms according to the invention may beused in medicine, e.g. as an analgesic. The particle(s) A and dosageforms are therefore particularly suitable for the treatment ormanagement of pain. In such dosage forms, the pharmacologically activeingredient a is preferably an analgesic.

A further aspect according to the invention relates to the dosage formas described above for use in the treatment of pain. A further aspect ofthe invention relates to the use of a pharmacologically activeingredient a and/or of an optionally present pharmacologically activeingredient b for the manufacture of a dosage form according to theinvention for the treatment of pain. A further aspect of the inventionrelates to a method for the treatment of pain comprising theadministration, preferably oral administration of a dosage formaccording to the invention to a subject in need thereof.

A further aspect according to the invention relates to the use of adosage form according to the invention for avoiding or hindering theabuse of the pharmacologically active ingredient a and optionally alsoof the optionally present pharmacologically active ingredient bcontained therein.

A further aspect according to the invention relates to the use of adosage form according to the invention for avoiding or hindering theunintentional overdose of the pharmacologically active ingredient acontained therein.

In this regard, the invention also relates to the use of apharmacologically active ingredient a and/or of an optionally presentpharmacologically active ingredient b for the manufacture of the dosageform according to the invention for the prophylaxis and/or the treatmentof a disorder, thereby preventing an overdose of the pharmacologicallyactive ingredient a, particularly due to comminution of the dosage formby mechanical action.

Another aspect of the invention relates to the use of a pharmaceuticaldosage form according to the invention as described above for theprevention of an overdose of pharmacologically active ingredient a afteraccidental or intentional simultaneous administration of a plurality ofthe dosage forms containing an overall supratherapeutic dose of thepharmacologically active ingredient a.

Another aspect of the invention relates to method for the prevention ofan overdose of pharmacologically active ingredient a after accidental orintentional simultaneous administration of a plurality of dosage formscontaining an overall supratherapeutic dose of the pharmacologicallyactive ingredient a, the method comprising the provision of apharmaceutical dosage form according to the invention as describedabove.

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

Inventive Example 1 and Comparative Example 1 both relate to acombination comprising 10 mg hydrocodone and 325 mg acetaminophen.Comparative Example 1 is based on a commercial product.

Inventive Example 2 and Comparative Example 2 both relate to acombination comprising 5 mg hydrocodone and acetaminophen. InventiveExample 2 relates to a dose of 325 mg acetaminophen, whereas ComparativeExample 2 relates to a dose of 300 mg acetaminophen. This minordifference, however, is not significant for the effect as demonstratedby this comparative experimental setting. Comparative Example 2 is basedon a commercial product.

Inventive Example 3 and Comparative Example 3 both relate to acomposition containing 10 mg amphetamine as the only pharmacologicallyactive ingredient. Comparative Example 3 is based on a commercialproduct.

Inventive Example 1—{10 mg Hydrocodone+325 mg Acetaminophen}

Tablets containing a combination of hydrocodone with acetaminophen weremanufactured from

-   -   hot melt extruded pellets comprising hydrocodone (particles A        comprising pharmacologically active ingredient a);    -   granules comprising acetaminophen (pharmacologically active        ingredient b); and    -   powder.

Powder mixtures of the various ingredients for the pellets weremanufactured by weighing (10 kg balance), sieving (1.0 mm hand sieve)and blending. The thus obtained powder mixtures were then hot-meltextruded (twin-screw extruder, Leistritz ZSE 18, blunt ends of kneadingelements, and extrusion diameter of 8×0.8 mm). The extrusion parametersare summarized in the table here below:

Extrusion parameter set: Extrusion temperature [° C.] 100-135° C. nozzle[° C.] 135 speed screw [rpm] 100 die diameter [mm] 0.8

The thus obtained cut extrudates were pelletized (LMP).

The granules comprising acetaminophen were separately prepared byconventional granulation. A powder mixture comprising acetaminophen wasprepared and thoroughly blended by means of a rapid mixer/granulator(Diosna® P10-60, chopper switched off) for 5 min at 90 rpm. Agranulation solution was prepared from purified water and hypromellose.The solution was stirred for 15 min at 550 rpm and 70° C. The powdermixture was granulated by adding the granulation solution over 1:30 minin the rapid mixer/granulator (Diosna® P10-60, chopper at 500 rpm) for 5min at 135 rpm.

The pellets were then mixed with the granules and with powder and thethus obtained mixture was subsequently compressed to tablets (KorschXL400). The tabletting parameters are summarized in the table herebelow:

Tablet form: tableting parameter set: Tablet weight = 708.2 mg tabletweight [mg] 708.2 Punch form = oblong 7 × 17 mm WR 4.5 breaking strength(tablet) [N] 86 without engraving

The compositions of the hot-melt extruded pellets, the granules and thepowder as well as their relative contents in the overall tablets aresummarized in the table here below:

per tablet [mg] form per tablet [mg] Substance Amount [%] 180.00 Pellets10.00 hydrocodone 25.42 bitartrate 1.44 citric acid 24.70 polyglycol6000 0.36 α-tocopherole 9.00 xanthan gum 98.50 polyethylene oxide 7 mio.36.00 croscarmellose sodium 528.20 Outer matrix 325.00 acetaminiophen57.23 30.00 croscarmellose sodium 45.00 microcrystalline cellulose, type101 5.29 hypromellose 2.28 magnesium stearate 0.32 6.90 silicondioxide0.97 113.73 microcrystalline 16.06 cellulose, type 101 708.20 100.00

While a dose of 10 mg hydrocodone in combination with a dose of 325 mgacetaminophen is a therapeutic dose, a plurality of such dosage formscontains an overall supratherapeutic dose of hydrocodone andacetaminophen.

In order to simulate the situation after accidental or intentionalsimultaneous administration of a plurality of the dosage forms accordingto Inventive Example 1, the in vitro release profiles were measuredunder modified conditions. The testing conditions were varied,particularly with respect to the overall volume of the release medium(900 mL, 600 mL, and 250 mL). The in vitro release profiles of thesedosage forms were measured at 37° C. by means of a paddle apparatuswithout sinker in 0.1 M HCl (in each case number of replicates n=3).Unless expressly stated otherwise, the paddle speed was adjusted to 25rpm. The results of the in vitro release measurements are shown in thetables here below.

Condition a) 25 rpm, 900 mL:

Hydrocodone—Pharmacologically Active Ingredient a:

1 5 tablets 10 tablets 1 5 10 tablet [mg] [mg] tablet tablets tabletsmean [mg] per tablet all 5 per tablet all 10 [%] [%] [%] 0 min 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 15 min 3.33 1.61 8.05 0.89 8.93 33.2916.08 8.89 30 min 4.13 1.97 9.83 1.20 12.00 41.33 19.70 12.01 60 min4.87 2.43 12.17 1.46 14.63 48.69 24.35 14.64

It becomes clear from the above data that the dosage forms according toInventive Example 1 are useful for avoiding overdose upon multipledosing. For example, while a single dosage form has released 4.13 mghydrocodone after 30 minutes, when a multitude of 5 dosage forms istested thereby simulating 5-fold multiple dosing, one dosage form withinthe group of 5 dosage form has released only 1.97 mg hydrocodone after30 minutes. When a multitude of 10 dosage forms is tested therebysimulating 10-fold multiple dosing, one dosage form within the group of10 dosage forms has even only released 1.20 mg hydrocodone after 30minutes.

Acetaminophen—Pharmacologically Active Ingredient b:

1 5 tablets 10 tablets 1 5 10 tablet [mg] [mg] tablet tablets tabletsmean [mg] per tablet all 5 per tablet all 10 [%] [%] [%] 0 min 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 15 min 101.16 50.91 254.53 31.36 313.5731.12 15.67 9.65 30 min 123.13 60.74 303.68 51.20 511.97 37.89 18.6915.75 60 min 141.62 72.39 361.97 45.53 455.27 43.58 22.28 14.01

It becomes clear from the above data that the dosage forms according toInventive Example 1 are useful for avoiding overdose upon multipledosing of both pharmacologically active ingredients. For example, whilea single dosage form has released 123.13 mg acetaminophen after 30minutes, when a multitude of 5 dosage forms is tested thereby simulating5-fold multiple dosing, one dosage form within the group of 5 dosageform has released only 60.74 mg acetaminophen after 30 minutes. When amultitude of 10 dosage forms is tested thereby simulating 10-foldmultiple dosing, one dosage form within the group of 10 dosage forms haseven only released 51.20 mg acetaminophen after 30 minutes.

Thus, as demonstrated by the above data, the advantages of the dosageform according to the invention do not only affect the pharmacologicallyactive ingredient a that is embedded in the polyalkylene oxide inparticle(s) A, but also the optionally present pharmacologically activeingredient b that may be present elsewhere in the dosage form.

The in vitro release profiles with respect to the release of hydrocodone(pharmacologically active ingredient a) are shown in FIG. 3. The invitro release profiles with respect to the release of acetaminophen(optionally present pharmacologically active ingredient b) are shown inFIG. 4.

Condition b) 25 rpm, 600 mL:

Hydrocodone—Pharmacologically Active Ingredient a:

1 5 tablets 10 tablets 1 5 10 tablet [mg] [mg] tablet tablets tabletsmean [mg] per tablet all 5 per tablet all 10 [%] [%] [%] 0 min 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 15 min 3.80 1.57 7.85 0.98 9.80 37.9715.72 9.80 30 min 4.65 1.94 9.68 1.32 13.23 46.45 19.36 13.23 60 min5.57 2.36 11.80 1.65 16.53 55.67 23.60 16.52

Acetaminophen—Pharmacologically Active Ingredient b:

1 5 tablets 10 tablets 1 5 10 tablet [mg] [mg] tablet tablets tabletsmean [mg] per tablet all 5 per tablet all 10 [%] [%] [%] 0 min 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 15 min 105.72 52.13 260.65 37.04 370.3732.53 16.04 11.39 30 min 128.05 64.27 321.35 45.64 456.40 39.40 19.7814.04 60 min 150.39 76.09 380.45 53.13 531.30 46.27 23.41 16.35

Condition c) 25 rpm, 250 mL:

Hydrocodone—Pharmacologically Active Ingredient a:

1 5 tablets 10 tablets 1 5 10 tablet [mg] [mg] tablet tablets tabletsmean [mg] per tablet all 5 per tablet all 10 [%] [%] [%] 0 min 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 15 min 2.96 1.34 6.68 1.22 12.23 29.6313.39 12.24 30 min 4.25 1.76 8.78 1.61 16.10 42.51 17.57 16.06 60 min5.14 2.28 11.38 1.97 19.73 51.39 22.78 19.73

Acetaminophen—Pharmacologically Active Ingredient b:

1 5 tablets 10 tablets 1 5 10 tablet [mg] [mg] tablet tablets tabletsmean [mg] per tablet all 5 per tablet all 10 [%] [%] [%] 0 min 0.00 0.000.00 0.00 0.00 0.00 0.00 0.00 15 min 122.35 62.82 314.08 57.73 577.3037.65 19.33 17.87 30 min 157.45 76.26 381.28 68.26 682.63 48.45 23.4621.01 60 min 177.57 91.23 456.15 76.67 766.70 54.64 28.07 23.59

Comparative Example 1 {10 mg Hydrocodone+325 mg Acetaminophen}

Commercial tablets (Norco®, Watson Pharma) containing the same dose ofhydrocodone and acetaminophen and having the following qualitativecomposition were tested for comparison:

Substance hydrocodone bitartrate acetaminophen croscannellose sodiumcrospovidone magnesium stearate cellulose, microcrystalline povidone Sstarch, corn stearic acid

The in vitro dissolution was tested in accordance with Example 1.

Condition 1: 50 rpm, 900 mL:

Hydrocodone—Pharmacologically Active Ingredient a:

1 tablet 10 tablets [mg] 1 tablet 10 tablets mean [mg] per tablet all 10[%] [%] 0 min 0.00 0.00 0.00 0.00 0.00 15 min 9.52 8.80 88.03 95.1788.03 30 min 9.45 9.57 95.70 94.56 95.69 60 min 9.52 9.41 94.13 95.1494.13

Acetaminophen—Pharmacologically Active Ingredient b:

1 tablet 10 tablets [mg] 1 tablet 10 tablets mean [mg] per tablet all 10[%] [%] 0 min 0.00 0.00 0.00 0.00 0.00 15 min 328.45 300.86 3008.63101.06 92.57 30 min 330.31 327.04 3270.37 101.63 100.63 60 min 330.15321.25 3212.50 101.59 98.85

Condition 2: 25 rpm, 250 mL:

Hydrocodone—Pharmacologically Active Ingredient a:

1 tablet 10 tablets [mg] 1 tablet 10 tablets mean [mg] per tablet all 10[%] [%] 0 min 0.00 0.00 0.00 0.00 0.00 15 min 4.47 4.19 41.93 44.7041.93 30 min 5.36 5.30 53.03 53.55 53.05 60 min 6.88 6.13 61.33 68.8061.33

Acetaminophen—Pharmacologically Active Ingredient b:

1 tablet 10 tablets [mg] 1 tablet 10 tablets mean [mg] per tablet all 10[%] [%] 0 min 0.00 0.00 0.00 0.00 0.00 15 min 142.07 133.69 1336.8743.71 41.13 30 min 178.55 177.74 1777.37 54.94 54.69 60 min 221.90207.28 2072.80 68.28 63.78

It becomes clear from the above data that the dosage forms according toComparative Example 1 are not useful for avoiding overdose upon multipledosing of both pharmacologically active ingredients. When a multitude of10 dosage forms is tested thereby simulating 10-fold multiple dosing,the release is not significantly altered (10 dosage forms according toComparative Example 1 vs. 1 dosage form according to Comparative Example1).

Inventive Example 2—{5 mg Hydrocodone+325 mg Acetaminophen}

In accordance with Inventive Example 1, tablets were prepared comprisinghot-melt extruded pellets, granules and powder as summarized in thetable here below containing 5 mg hydrocodone+325 mg acetaminophen:

per per tablet tablet Amount [mg] form [mg] Substance [%] 180.00 Pellets5.00 hydrocodone bitartrate 25.42 1.44 citric acid 26.50 macrogole 60000.36 α-tocopherole 9.00 xanthan gum 101.70 polyethylene oxide 7 mio.36.00 croscarmellose sodium 528.20 Outer 325.00 acetaminophen 57.23matrix 30.00 croscarmellose sodium 45.00 microcrystalline cellulose,type 101 5.29 hypromellose 2.28 magnesium stearate 0.32 6.90silicondioxide 0.97 113.73 microcrystalline cellulose, type 101 16.06708.20 100.00

Comparative Example 2 {5 mg Hydrocodone+300 mg Acetaminophen}

For comparative purposes, a commercial product (Vicodin®, AbbVie Inc.)containing the same dose of hydrocodone and 300 mg acetaminophen wastested.

In order to even more realistically simulate the situation in thegastrointestinal tract, the TIMagc system was used for testing release.The advanced gastric compartment of the TIMagc system realisticallysimulates gastric shape and motility and the consequent forces that areapplied to dosage forms and food. This compartment can be used asstandalone or as part of the TIM gastrointestinal systems to evaluatethe bio-accessibility (availability for absorption) of nutrients. TIM isthe dynamic in vitro gastro-intestinal model that simulates very closelythe successive conditions of the stomach and small intestine. In theTIMagc the luminal conditions in the stomach are accurately simulatedunder computer-controlled conditions. The TIMagc system was designed andvalidated for the in vivo situation (see Bellmann et al., Development ofan advanced in vitro model of the stomach for studying the gastricbehaviour of compounds. Food Res. Internat. 2016).

The following experiments were performed for the following testproducts:

hydrocodone/acetaminophen Fasted state Fed state 1 tablet of InventiveExample 2 1 tablet of Inventive Example 2 5 tablets of Inventive Example2 — 10 tablets of Inventive Example 2 10 tablets of Inventive Example 210 tablets of Comparative Example 2 (Vicodin ®) 10 tablets ofComparative Example 2 (Vicodin ®)

The duration of each experiment in the fasted state was 60 minutes, inthe fed state 180 minutes. Composition of the gastric intake (mealmatrix) fasted or fed state conditions and simulated gastric parametersfor each conditions are summarized in the table here below:

TIMagc Fed state Fasted state Intake (total) 300 g 270 g High fat meal(HFM) 150 g — Citrate buffer — 27 g Water 70 g 213 g Gastric startresidue 10 g 30 g Gastric electrolyte solution 70 g — Gastric emptyingT½ 80 min 20 min Gastric pH 6.5 to 1.7 in 180 min 3.0 to 1.8 in 30 min

The high fat meal (HFM) was used for fed state experiments asrecommended by the FDA for clinical studies (FDA, CDER Guidance forBioavailability and Fed Bioequivalence). This meal contained 50 energy %fat, 20 energy % protein and 30 energy % in the form of carbohydrates.The meal was composed of eggs, bacon, toast bread, potatoes, milk,butter and margarine. The meal was prepared as one batch, divided inportions (160 g) and stored below −18° C. Per TIMagc run one portion ofthe meal was used. Gastric secretions are composed of gastric enzymes,namely lipase, pepsin and (‘swallowed’) alpha-amylase, sodium acetatebuffer, as well as gastric electrolyte solution (NaCl, KCl, CaCl₂×2H₂O).Gastric starting fluid was composed of 15 g gastric electrolyte solutionand 15 g HPMC (0.4%) plus bile (0.04%).

The in vitro gastrointestinal model TIM equipped with the advancedgastric compartment was used. The compartment consisted of a body partand the distal and proximal antrum.

FIG. 7 schematically illustrates the TIMagc representing A: gastricbody; B: proximal antrum; C: distal (terminal) antrum; D: pyloricsphincter.

Removal and addition of warm water (37° C.) into the jacket results inperistaltic movements between the distal and proximal antrum. Gastricsecretions, comprising gastric enzymes and gastric acid entered theTIMagc in the gastric body (FIG. 7, part A). The TIMagc emptied overtime as a result of the pre-set gastric emptying curve according to thefed state or fasted state profile.

The gastric effluent was collected at the following time points: 5, 10,15, 20, 30, 45 and 60 minutes in the fasted state and at 10, 15, 20, 30,45, 60, 90, 120, 150, 180 minutes in the fed state. At the end of eachexperiment all residual material was collected by a pipet from theTIMagc and the compartment was rinsed once with 50 ml warm water.Withdrawn samples were directly treated for sample analysis by thesponsor.

The absolute amount of each pharmacologically active ingredient(hydrocodone and acetaminophen, respectively) recovered in the gastriceffluent was calculated by multiplying the analyzed concentration in thesample with the collected volume (equation 1). Data are expressed ascumulative percentage of the intake of pharmacologically activeingredient:

A(mg)=C _(sample)(μg/ml)·10⁻³ ·V _(sample)(ml)

The results of the duplicate TIMagc runs are presented as mean±range.

The numerical results (cumulative values) for hydrocodone are summarizedin the tables here below:

Hydrocodone Cumulative Amount [% LS]—Fasted State:

1 tablet 10 tables of inv. of inv. 1 tablet 10 tablets 10 tablets ex. 2in ex. 2 in of inv. ex. of inv. ex. 5 tablets of comp. ex. Time 0.1M0.1M 2 in blank 2 in blank of inv. ex. 2 in blank [min] HCl HCl #1 #2 #1#2 2 in blank #1 #2 5 0.52 0.12 0.51 0.17 0.17 0.56 0.16 0.16 0.16 103.25 0.70 2.04 1.17 0.66 1.93 0.90 0.40 0.93 15 6.61 1.76 4.67 3.48 1.583.13 1.97 2.52 3.11 20 11.50 3.14 8.22 6.27 3.81 4.86 3.68 7.12 6.72 3023.81 15.00 22.15 17.52 11.39 12.86 11.40 24.64 23.56 45 42.38 29.3540.32 38.94 28.49 25.02 30.01 54.75 52.36 60 60.12 44.08 58.75 54.7844.66 35.70 44.73 69.94 68.00 Residue 84.92 62.42 93.59 83.02 64.2955.44 70.58 86.91 90.36 Rinse 89.32 70.68 95.36 83.83 70.21 60.45 75.8990.48 93.06

Hydrocodone Cumulative Amount [% LS]—Fed State:

Time 1 tablet of 10 tablets of 10 tablets of [min] inv. ex. 2 inv. ex. 2comp. ex. 2 10 0.00 0.00 0.00 15 0.00 0.00 0.00 20 0.00 0.00 0.00 300.00 0.00 0.00 45 0.00 0.00 0.00 60 0.00 1.93 0.00 90 0.00 15.56 0.00120 44.31 50.53 55.57 150 67.24 78.52 82.31 180 93.15 91.72 94.38Residue 106.07 97.81 98.24 Rinse 106.78 98.20 99.26

The results for hydrocodone are also illustrated by FIGS. 8 to 10.

A comparison of the fasted state experiments for hydrocodone is shown inFIG. 8: Fasted state cumulative gastric effluent of hydrocodone aspercentage (%) of intake of 1 tablet (♦), 10 tablets (▪), 5 tablets (X)and Vicodin 10 tablets (▴), mean±range, n=2, hydrocodone 5 tablets: n=1,gastric emptying curve (black line).

A comparison of the fed state experiments for hydrocodone is shown inFIG. 9: Fed state cumulative gastric effluent of hydrocodone aspercentage (%) of intake of 1 tablet (♦), 10 tablets (▪) and Vicodin 10tablets (▴) state, n=1, gastric emptying curve (black line).

A comparison of fasted versus fed state experiments for hydrocodone isshown in FIGS. 10A, 10B and 10C: Fasted versus fed state cumulativegastric effluent of hydrocodone as percentage (%) of intake of 1 tablet(A), 10 tablets (B) and Vicodin 10 tablets (C) state, n=1, dotted linesindicate fasted state, solid lines indicate fed state, gastric emptyingcurve (black lines).

The numerical results (cumulative values) for acetaminophen aresummarized in the tables here below:

Acetaminophen Cumulative Amount [% LS] Fasted State:

1 tablet 10 tables of inv. of inv. 1 tablet 10 tablets 10 tablets 10tablets ex. 2 in ex. 2 in of inv. ex. of inv. ex. 5 tablets of comp. ex.of comp. ex. Time 0.1M 0.1M 2 in blank 2 in blank of inv. ex. 2 in blank2 in blank [min] HCl HCl #1 #2 #1 #2 2 in blank #1 #2 5 2.67 0.60 1.400.84 1.05 4.29 1.27 0.13 0.14 10 9.10 2.20 4.37 3.02 2.98 12.09 4.820.35 0.90 15 13.88 3.80 7.51 5.89 4.84 18.66 7.68 1.76 2.45 20 19.165.33 10.80 8.65 7.67 24.84 10.54 4.28 4.58 30 29.74 18.39 22.00 18.8616.19 38.85 19.72 14.45 14.78 45 44.95 32.43 37.11 39.96 32.66 53.4039.54 35.63 35.65 60 59.71 45.76 51.72 55.40 45.64 64.09 52.77 48.9048.91 Residue 77.60 59.35 76.86 79.54 59.47 79.01 73.00 68.20 72.53Rinse 83.47 65.68 81.99 84.89 64.14 82.58 77.45 82.39 83.89

Acetaminophen Cumulative Amount [% LS]—Fed State:

Time 1 tablet of 10 tablets of 10 tablets of [min] inv. ex. 2 inv. ex. 2comp. ex. 2 10 0.03 0.01 0.00 15 0.12 0.04 0.00 20 0.20 0.08 0.00 300.35 0.15 0.00 45 0.63 0.63 0.00 60 0.94 2.75 0.01 90 2.22 17.71 0.48120 37.27 49.09 39.72 150 58.46 71.41 63.09 180 84.56 82.47 74.34Residue 97.72 87.71 78.34 Rinse 98.70 88.17 79.76

The results for acetaminophen are illustrated by FIGS. 11 to 13.

A comparison of fasted state experiments for acetaminophen is shown inFIG. 11: Fasted state cumulative gastric effluent of acetaminophen aspercentage (%) of intake of 1 tablet (♦), 10 tablets (▪), 5 tablets (X)and Vicodin 10 tablets (▴), mean±range, n=2, acetaminophen 5 tablets:n=1, gastric emptying curve (black line).

A comparison of fed state experiments for acetaminophen is shown in FIG.12: Fed state cumulative gastric effluent of acetaminophen as percentage(%) of intake of 1 tablet (♦), 10 tablets (▪) and Vicodin 10 tablets (▴)state, n=1, gastric emptying curve (black line).

A comparison of fasted versus fed state experiments for acetaminophen isshown in FIGS. 13A, 13B and 13C: Fasted versus fed state cumulativegastric effluent of acetaminophen as percentage (%) of intake of 1tablet (A), 10 tablets (B) and Vicodin 10 tablets (C) state, n=1, dottedlines indicate fasted state, solid line indicate fed state, gastricemptying curve (black line).

It becomes clear from the above data that the dosage forms according toInventive Example 2 are useful for avoiding overdose upon multipledosing of both pharmacologically active ingredients, whereas thecommercial dosage forms according to Comparative Example 2 are notuseful for that purpose.

Inventive Example 3—{10 mg Amphetamine}

In accordance with Inventive Examples 1 and 2, pellets having thefollowing composition were prepared and coated with a protective coating(Opadry®):

per capsule mg wt.-% amphetamine sulfate 10.00 7.76 polyethylene oxideM_(r) 7 mio 67.32 52.21 macrogole 6000 16.03 12.43 α-tocopherole 0.240.19 pregelatinized maize starch 26.41 20.48 Opadry ® clear 85F 8.936.93 128.93 100.00

The pellets were filled into capsules (Capsugel® transparent, conisnap), size 2.

Comparative Example 3 {10 mg Amphetamine}

For comparative purposes, commercial tablets (Evekeo®, ArborPharmaceuticals) containing the same dose of amphetamine sulfate weretested.

In accordance with Inventive Example 2 and Comparative Example 2 (TIMagcsystem), the following experiments were performed for the following testproducts (the capsules/tablets were tested as such as well as thepellets contained in such capsules after removal of the capsule):

amphetamine (capsules) Fasted state Fed state 1 capsule of InventiveExample 3 1 capsule of Inventive Example 3 10 capsules of InventiveExample 3 10 capsules of Inventive Example 3 10 tablets of ComparativeExample 3 (Evekeo ®) 10 tablets of Comparative Example 3 (Evekeo ®)amphetamine (pellets) Fasted state 1 capsule content of InventiveExample 3 10 capsules content of Inventive Example 3

The numerical results (cumulative values) for amphetamine are summarizedin the tables here below:

Amphetamine Cumulative Amount [% LS]—Fasted State:

1 capsule 10 capsules pellets of pellets of of inv. ex. of inv. ex. 1capsule 10 capsules 10 tablets 1 capsule 10 capsules Time 3 in 0.1M 3 in0.1M of inv. ex. of inv. ex. of comp. ex. of inv. ex. of inv. ex. [min]HCl HCl 3 in blank 3 in blank 3 in blank 3 in blank 3 in blank 5 0.12n.d. 0.14 0.13 1.84 1.75 0.76 10 4.07 1.36 3.79 2.62 8.63 9.55 4.08 1514.61 3.71 10.88 7.88 16.38 20.27 8.72 20 25.63 7.91 21.94 14.31 24.8930.05 14.79 30 42.17 26.51 39.17 30.87 42.76 49.49 29.13 45 61.58 48.9160.09 53.78 64.39 67.98 47.49 60 73.24 65.15 74.63 65.70 76.41 79.9461.01 Residue 84.57 84.52 93.41 85.38 93.76 95.90 79.82 Rinse 86.6986.51 93.90 86.96 94.30 97.18 80.86

Amphetamine Cumulative Amount [% LS]—Fed State:

Time 1 capsule of 10 capsules of 10 tablets of [min] inv. ex. 3 inv. ex.3 comp. ex. 3 30 0.89 3.16 9.45 45 5.32 9.42 19.95 60 16.89 20.32 33.8690 65.62 58.88 55.21 120 81.51 77.69 80.94 150 87.79 90.50 94.39 18091.78 95.26 99.90 Residue 94.08 96.77 101.90 Rinse 94.08 97.29 102.33

The results for amphetamine capsules/tablets are also illustrated byFIGS. 14 to 16.

A comparison of fasted state experiments for amphetamine (capsules) isshown in FIG. 14: Fasted state cumulative gastric effluent ofamphetamine as percentage (%) of intake of amphetamine of 1 capsule (♦),10 capsules (▪) and Evekeo 10 tablets (▴), n=1, gastric emptying curve(black line).

A comparison of fed state experiments for amphetamine (capsules) isshown in FIG. 15: Fed state cumulative gastric effluent of amphetamineas percentage (%) of intake of amphetamine of 1 capsule (♦), 10 capsules(▪) and Evekeo 10 tablets (▴), n=1, gastric emptying curve (black line).

A comparison of fasted versus fed state experiments for amphetamine(capsules/tablets) is shown in FIGS. 16A, 16B and 16C: Fasted versus fedstate cumulative gastric effluent of amphetamine as percentage (%) ofintake of amphetamine of 1 capsule (A), 10 capsules (B) and Evekeo 10tablets (C), n=1, dotted lines indicate fasted state, solid lineindicate fed state, gastric emptying curve (black lines).

The results for the separated amphetamine pellets are illustrated byFIG. 17. A comparison of fasted state experiments for amphetamine(pellets) is shown in FIG. 17: Fasted state cumulative gastric effluentof amphetamine as percentage (%) of intake of amphetamine of pellets of1 capsule (X) and pellets of 10 capsules (*), n=1, gastric emptyingcurve (black line).

It becomes clear from the above data that the dosage forms according toInventive Example 3 are useful for avoiding overdose upon multipledosing of the pharmacologically active ingredient, whereas thecommercial dosage forms according to Comparative Example 3 are notuseful for that purpose.

It can be concluded from a comparison of Inventive Example 2 withComparative Example 2 and from a comparison of Inventive Example 3 withComparative Example 3 that under simulated fed state in vitro conditions(filled stomach), the residence time of the dosage forms corresponds tothe stomach emptying intervals independent of the number of dosage formsthat are contained in the stomach, i.e. that are administeredsimultaneously. However, under such fed state conditions a potentialabuser cannot achieve the desired kick anyway so that these conditionsare not relevant for a potential abuser.

In contrast, under simulated fasted state in vitro conditions, which arerelevant for a potential abuser, the number of dosage forms that arecontained in the stomach, i.e. that are administered simultaneously, canbe distinguished from one another (1 vs. 5 vs. 10). For avoidingoverdosing, the residence time in the stomach is of clinical relevance.The longer the residence time in the stomach, the more difficult (lesslikely) it is to achieve the desired “kick” by simultaneouslyadministering a plurality of dosage forms.

The experimental data demonstrate that the inventive formulationsprovide an extended residence time in the stomach when administeredsimultaneously as a plurality, whereas the comparative formulations donot show such an extended residence time in the stomach.

1. A pharmaceutical dosage form comprising a pharmacologically activeingredient a, said pharmacologically active ingredient a being selectedfrom the group consisting of amphetamine and physiologically acceptablesalts thereof, at least a portion of the pharmacologically activeingredient a being contained in one or more particles A, each of saidone or more particles A comprising a homogeneous mixture of thepharmacologically active ingredient a, one or more disintegrants and apolymer matrix, the one or more disintegrants being present in an amountof 10-30 wt % based on a total weight of the one or more particles A,the polymer matrix comprising a polyethylene oxide having an averagemolecular weight of at least 200,000 g/mol, the polyethylene oxide beingpresent in an amount of at least 40 wt %, based on a total weight of theone or more particles A, the one or more particles A not comprisinghydroxypropylmethyl cellulose, the one or more particles A notcomprising a wax, and the one or more particles A having a breakingstrength of at least 300 N; said dosage form being adapted to prevent anoverdose of the pharmacologically active ingredient a after accidentalor intentional simultaneous administration of a plurality of the dosageforms containing an overall supratherapeutic dose of thepharmacologically active ingredient a.
 2. The pharmaceutical dosage formaccording to claim 1, wherein the one or more disintegrants are selectedfrom the group consisting of starches, starch derivatives, cellulosederivatives, and gas releasing substances.
 3. The pharmaceutical dosageform according to claim 2, wherein the one or more disintegrants areselected from the group consisting of maize starch, pregelatinizedstarch, sodium starch glycolate, croscarmellose sodium, and sodiumbicarbonate.
 4. The pharmaceutical dosage form according to claim 3,wherein the disintegrant is pregelatinized starch.
 5. The pharmaceuticaldosage form according to claim 1, wherein the polyalkylene oxide has anaverage molecular weight of at least 500,000 g/mol.
 6. Thepharmaceutical dosage form according to claim 5, wherein thepolyalkylene oxide has an average molecular weight in the range of1,000,000 g/mol to 15,000,000 g/mol.
 7. The pharmaceutical dosage formaccording to claim 1, wherein the content of the polyalkylene oxide inthe dosage form amounts to at least 25 mg.
 8. The pharmaceutical dosageform according to claim 7, wherein the content of the polyalkylene oxidein the dosage form amounts to at least 50 mg.
 9. The pharmaceuticaldosage form according to claim 1, wherein the one or more particles Aamount to a total number within the range of from 20 to
 600. 10. Thepharmaceutical dosage form according to claim 1, wherein the one or moreparticles A amount to a total content of at least 25 wt.-%, based on thetotal weight of the dosage form.
 11. The pharmaceutical dosage formaccording to claim 1, wherein the one or more particles A aretamper-resistant as such so that they also provide tamper-resistanceafter they have been separated from the remaining constituents of thedosage form.
 12. The pharmaceutical dosage form according to claim 1,wherein the one or more particles A contain the total amount of thepharmacologically active ingredient a that is contained in the dosageform.
 13. The pharmaceutical dosage form according to claim 1, whereinthe one or more particles A are thermoformed by hot-melt extrusion. 14.The pharmaceutical dosage form according to claim 1, wherein each ofsaid intact dosage forms additionally contains a pharmacologicallyactive ingredient b which differs from the pharmacologically activeingredient a.
 15. The pharmaceutical dosage form according to claim 14,wherein the pharmacologically active ingredient b is selected from thegroup consisting of acetylsalicylic acid, aloxiprin, choline salicylate,sodium salicylate, salicylamide, salsalate, ethenzamide, morpholinesalicylate, dipyrocetyl, benorilate, diflunisal, potassium salicylate,guacetisal, carbasalate calcium, imidazole salicylate, phenazone,metamizole sodium, aminophenazone, propyphenazone, nifenazone,acetaminophen (paracetamol), phenacetin, bucetin, propacetamol,rimazolium, glafenine, floctafenine, viminol, nefopam, flupirtine,ziconotide, methoxyflurane, nabiximols, dihydroergotamine, ergotamine,methysergide, lisuride, flumedroxone, sumatriptan, naratriptan,zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan,pizotifen, clonidine, iprazochrome, dimetotiazine, oxetorone,phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebuzone,indomethacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac,bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpiramide,oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac, piroxicam,tenoxicam, droxicam, lornoxicam, meloxicam, ibuprofen, naproxen,ketoprofen, fenoprofen, fenbufen, benoxaprofen, suprofen, pirprofen,flurbiprofen, indoprofen, tiaprofenic acid, oxaprozin, ibuproxam,dexibuprofen, flunoxaprofen, alminoprofen, dexketoprofen, naproxcinod,mefenamic acid, tolfenamic acid, flufenamic acid, meclofenamic acid,celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib,nabumetone, niflumic acid, azapropazone, glucosamine, benzydamine,glucosaminoglycan polysulfate, proquazone, orgotein, nimesulide,feprazone, diacerein, morniflumate, tenidap, oxaceprol, chondroitinsulfate, oxycinchophen, sodium aurothiomalate, sodium aurotiosulfate,auranofin, aurothioglucose, aurotioprol, penicillamine, bucillamine,their physiologically acceptable salts, and mixtures thereof.
 16. Thepharmaceutical dosage form according to claim 1, wherein the one or moreparticles A comprise an antioxidant.
 17. The pharmaceutical dosage formaccording to claim 16, wherein the antioxidant is selected from thegroup consisting of ascorbic acid, butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), salts of ascorbic acid,monothioglycerol, phosphorous acid, vitamin C, vitamin E and thederivatives thereof, coniferyl benzoate, nordihydroguajaretic acid,gallus acid esters, and sodium bisulfite.
 18. The pharmaceutical dosageform according to claim 1, wherein the one or more particles A comprisean antioxidant.
 19. The pharmaceutical dosage form according to claim 1,wherein the one or more particles A cannot be comminuted with a hammeror with a mortar and pestle.
 20. The pharmaceutical dosage fromaccording to claim 1, which is a capsule.
 21. The pharmaceutical dosageform according to claim 1, which is a tablet.
 22. A method for reducingthe risk that a human subject will suffer an overdose ofpharmacologically active ingredient a after accidental or intentionalsimultaneous administration of a plurality of intact dosage formscontaining in combination an overall supratherapeutic dose of thepharmacologically active ingredient a, said pharmacologically activeingredient a being selected from the group consisting of amphetamine andphysiologically acceptable salts thereof, at least a portion of thepharmacologically active ingredient a being contained in one or moreparticles A, each of said one or more particles A comprising ahomogeneous mixture of the pharmacologically active ingredient a, one ormore disintegrants and a polymer matrix, the one or more disintegrantsbeing present in an amount of 10-30 wt % based on a total weight of theone or more particles A, the polymer matrix comprising a polyethyleneoxide having an average molecular weight of at least 200,000 g/mol, thepolyethylene oxide being present in an amount of at least 40 wt %, basedon a total weight of the one or more particles A, the one or moreparticles A not comprising hydroxypropylmethyl cellulose, the one ormore particles A not comprising a wax, and the one or more particles Ahaving a breaking strength of at least 300 N, and said method comprising(a) administering to said human subject said plurality of intact dosageforms containing in combination an overall supratherapeutic dose of thepharmacologically active ingredient a and (b) achieving as a result saidadministering of said plurality of intact dosage forms to said humansubject does not cause said human subject to suffer an overdose of thepharmacologically active ingredient a.
 23. The method according to claim22, wherein each of said intact dosage forms is a capsule.
 24. Themethod according to claim 22, wherein each of said intact dosage formsis a tablet.